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Pharmaceuticals
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Antiviral Drugs 2021
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Antiviral Drugs 2021

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 89351

Special Issue Editor

Dr. Grigoris Zoidis

E-Mail Website
Guest Editor
Division of Pharmaceutical Chemistry, Department of Pharmacy, Panepistimiopolis Zografou, 15771 Athens, Greece
Interests: medicinal chemistry; antiviral agents; anticancer agents; trypanocidal agents; anti-HBV drugs; anti-HCV drugs; anti-influenza A agents; anti-flavivirus agents
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

From the beginning of human civilization, viral infections have been part of human life, and still represent one of the greatest burdens for humans and society, with a huge devastating socioeconomic impact. Over the last year, a worst-case scenario of viral pandemic (i.e., severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has threatened millions of lives, while devastating the primal health care systems across the world. Fortunately, the advancement in the field of antiviral drug discovery over the last forty years led to the development of important therapies that intercept human immunodeficiency virus (HIV) replication or cure hepatitis C virus infections in people suffering from liver disease. Nevertheless, according to the World Health Organization (WHO), we are still a long way from achieving suitable treatments for other viral-infection-related diseases such as SARS, HBV, Influenza, and Ebola. Moreover, the emergence of drug resistance that threatens the efficacy of successful therapies used today and the lack of vaccines for many viral pathogens make the discovery and development of antiviral agents an unmet global need. Urged by this global crisis, the field has been involved in an unprecedented endeavor to enhance established antiviral strategies and develop novel and innovative approaches for new classes of antiviral agents targeting different life cycle pathways that are critical for the virus, including viral and host factors and new antiviral modalities.

In the present Special Issue entitled “Antiviral Drugs”, we are inviting the submission of original research articles, letters, and/or reviews from academia, research institutes, not-for-profit organizations, or industry that work on the identification, synthesis, and evaluation of direct-acting antiviral or host-targeting agents that inhibit viral replication or pathogenesis. Furthermore, we also welcome the submission of mechanistic studies of new small organic molecules, metal complexes, and natural products, as well as studies on drug resistance, the in silico design of antiviral agents, and antiviral target validation.

Prof. Dr. Grigoris Zoidis
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (21 papers)

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39 pages, 12684 KiB  
Article
Novel Lipophilic Hydroxamates Based on Spirocarbocyclic Hydantoin Scaffolds with Potent Antiviral and Trypanocidal Activity
by Vasiliki Pardali, Erofili Giannakopoulou, George Mpekoulis, Vassilina Tsopela, Georgios Panos, Martin C. Taylor, John M. Kelly, Niki Vassilaki and Grigoris Zoidis
Pharmaceuticals 2023, 16(7), 1046; https://0-doi-org.brum.beds.ac.uk/10.3390/ph16071046 - 24 Jul 2023
Viewed by 1665
Abstract
Flaviviridae infections, such as those caused by hepatitis C (HCV) and dengue viruses (DENVs), represent global health risks. Infected people are in danger of developing chronic liver failure or hemorrhagic fever, both of which can be fatal if not treated. The tropical parasites [...] Read more.
Flaviviridae infections, such as those caused by hepatitis C (HCV) and dengue viruses (DENVs), represent global health risks. Infected people are in danger of developing chronic liver failure or hemorrhagic fever, both of which can be fatal if not treated. The tropical parasites Trypanosoma brucei and Trypanosoma cruzi cause enormous socioeconomic burdens in Sub-Saharan Africa and Latin America. Anti-HCV chemotherapy has severe adverse effects and is expensive, whereas dengue has no clinically authorized treatment. Antiparasitic medicines are often toxic and difficult to administer, and treatment failures are widely reported. There is an urgent need for new chemotherapies. Based on our previous research, we have undertaken structural modification of lead compound V with the goal of producing derivatives with both antiviral and trypanocidal activity. The novel spirocarbocyclic-substituted hydantoin analogs were designed, synthesized, and tested for antiviral activity against three HCV genotypes (1b, 3a, 4a), DENV, yellow fever virus (YFV), and two trypanosome species (T. brucei, T. cruzi). The optimization was successful and led to compounds with significant antiviral and trypanocidal activity and exceptional selectivity. Several modifications were made to further investigate the structure–activity relationships (SARs) and confirm the critical role of lipophilicity and conformational degrees of freedom. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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16 pages, 1201 KiB  
Article
SARS-CoV-2 Inhibitors Identified by Phenotypic Analysis of a Collection of Viral RNA-Binding Molecules
by Alvaro Simba-Lahuasi, Ángel Cantero-Camacho, Romel Rosales, Briana Lynn McGovern, M. Luis Rodríguez, Vicente Marchán, Kris M. White, Adolfo García-Sastre and José Gallego
Pharmaceuticals 2022, 15(12), 1448; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15121448 - 22 Nov 2022
Cited by 1 | Viewed by 1828
Abstract
Antiviral agents are needed for the treatment of SARS-CoV-2 infections and to control other coronavirus outbreaks that may occur in the future. Here we report the identification and characterization of RNA-binding compounds that inhibit SARS-CoV-2 replication. The compounds were detected by screening a [...] Read more.
Antiviral agents are needed for the treatment of SARS-CoV-2 infections and to control other coronavirus outbreaks that may occur in the future. Here we report the identification and characterization of RNA-binding compounds that inhibit SARS-CoV-2 replication. The compounds were detected by screening a small library of antiviral compounds previously shown to bind HIV-1 or HCV RNA elements with a live-virus cellular assay detecting inhibition of SARS-CoV-2 replication. These experiments allowed detection of eight compounds with promising anti-SARS-CoV-2 activity in the sub-micromolar to micromolar range and wide selectivity indexes. Examination of the mechanism of action of three selected hit compounds excluded action on the entry or egress stages of the virus replication cycle and confirmed recognition by two of the molecules of conserved RNA elements of the SARS-CoV-2 genome, including the highly conserved S2m hairpin located in the 3’-untranslated region of the virus. While further studies are needed to clarify the mechanism of action responsible for antiviral activity, these results facilitate the discovery of RNA-targeted antivirals and provide new chemical scaffolds for developing therapeutic agents against coronaviruses. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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14 pages, 1486 KiB  
Article
Cationic Perylene Antivirals with Aqueous Solubility for Studies In Vivo
by Anna A. Shtro, Anzhelika V. Garshinina, Vera A. Alferova, Polina N. Kamzeeva, Viktor P. Volok, Ekaterina S. Kolpakova, Timofei D. Nikitin, Alexey A. Chistov, Evgeny S. Belyaev, Vladimir A. Korshun, Liubov I. Kozlovskaya and Andrey V. Aralov
Pharmaceuticals 2022, 15(10), 1178; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15101178 - 22 Sep 2022
Cited by 3 | Viewed by 1700
Abstract
Perylene-based compounds are attracting significant attention due to their high broad-spectrum antiviral activity against enveloped viruses. Despite unambiguous results of in vitro studies and high selectivity index, the poor water solubility of these compounds prevented in vivo evaluation of their antiviral properties. In [...] Read more.
Perylene-based compounds are attracting significant attention due to their high broad-spectrum antiviral activity against enveloped viruses. Despite unambiguous results of in vitro studies and high selectivity index, the poor water solubility of these compounds prevented in vivo evaluation of their antiviral properties. In this work, we synthesized a series of compounds with a perylene pharmacophore bearing positively charged substituents to improve the aqueous solubility of this unique type of antivirals. Three types of charged groups were introduced: (1) quaternary morpholinium salts (3a–b); (2) a 2′-O-l-valinyl-uridine hydrochloride residue (8), and (3) a 3-methylbenzothiazolium cation (10). The synthesized compounds were evaluated based both on antiviral properties in vitro (CHIKV, SARS-CoV-2, and IAV) and on solubility in aqueous media. Compound 10 has the greatest aqueous solubility, making it preferable for pre-evaluation by intragastrical administration in a mouse model of lethal influenza pneumonia. The results indicate that the introduction of a positively charged group is a viable strategy for the design of drug candidates with a perylene scaffold for in vivo studies. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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11 pages, 1789 KiB  
Article
Vemurafenib Inhibits Enterovirus A71 Genome Replication and Virus Assembly
by Bodan Hu, Kenn Ka-Heng Chik, Jasper Fuk-Woo Chan, Jian-Piao Cai, Hehe Cao, Jessica Oi-Ling Tsang, Zijiao Zou, Yin-Po Hung, Kaiming Tang, Lilong Jia, Cuiting Luo, Feifei Yin, Zi-Wei Ye, Hin Chu, Man-Lung Yeung and Shuofeng Yuan
Pharmaceuticals 2022, 15(9), 1067; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091067 - 27 Aug 2022
Cited by 2 | Viewed by 1868
Abstract
Enterovirus A71 (EV-A71) infection is a major cause of hand, foot, and mouth disease (HFMD), which may be occasionally associated with severe neurological complications. There is currently a lack of treatment options for EV-A71 infection. The Raf-MEK-ERK signaling pathway, in addition to its [...] Read more.
Enterovirus A71 (EV-A71) infection is a major cause of hand, foot, and mouth disease (HFMD), which may be occasionally associated with severe neurological complications. There is currently a lack of treatment options for EV-A71 infection. The Raf-MEK-ERK signaling pathway, in addition to its critical importance in the regulation of cell growth, differentiation, and survival, has been shown to be essential for virus replication. In this study, we investigated the anti-EV-A71 activity of vemurafenib, a clinically approved B-Raf inhibitor used in the treatment of late-stage melanoma. Vemurafenib exhibits potent anti-EV-A71 effect in cytopathic effect inhibition and viral load reduction assays, with half maximal effective concentration (EC50) at nanomolar concentrations. Mechanistically, vemurafenib interrupts both EV-A71 genome replication and assembly. These findings expand the list of potential antiviral candidates of anti-EV-A71 therapeutics. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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12 pages, 7576 KiB  
Article
A Peptide Inhibitor of the Human Cytomegalovirus Core Nuclear Egress Complex
by Sewar Alkhashrom, Jintawee Kicuntod, Katharina Stillger, Tamara Lützenburg, Christian Anzenhofer, Ines Neundorf, Manfred Marschall and Jutta Eichler
Pharmaceuticals 2022, 15(9), 1040; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15091040 - 23 Aug 2022
Cited by 9 | Viewed by 3008
Abstract
The replication of human cytomegalovirus (HCMV) involves a process termed nuclear egress, which enables translocation of newly formed viral capsids from the nucleus into the cytoplasm. The HCMV core nuclear egress complex (core NEC), a heterodimer of viral proteins pUL50 and pUL53, is [...] Read more.
The replication of human cytomegalovirus (HCMV) involves a process termed nuclear egress, which enables translocation of newly formed viral capsids from the nucleus into the cytoplasm. The HCMV core nuclear egress complex (core NEC), a heterodimer of viral proteins pUL50 and pUL53, is therefore considered a promising target for new antiviral drugs. We have recently shown that a 29-mer peptide presenting an N-terminal alpha-helical hook-like segment of pUL53, through which pUL53 interacts with pUL50, binds to pUL50 with high affinity, and inhibits the pUL50–pUL53 interaction in vitro. Here, we show that this peptide is also able to interfere with HCMV infection of cells, as well as with core NEC formation in HCMV-infected cells. As the target of the peptide, i.e., the pUL50–pUL53 interaction, is localized at the inner nuclear membrane of the cell, the peptide had to be equipped with translocation moieties that facilitate peptide uptake into the cell and the nucleus, respectively. For the resulting fusion peptide (NLS-CPP-Hook), specific cellular and nuclear uptake into HFF cells, as well as inhibition of infection with HCMV, could be demonstrated, further substantiating the HCMV core NEC as a potential antiviral target. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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24 pages, 2618 KiB  
Article
A Versatile Class of 1,4,4-Trisubstituted Piperidines Block Coronavirus Replication In Vitro
by Sonia De Castro, Annelies Stevaert, Miguel Maldonado, Adrien Delpal, Julie Vandeput, Benjamin Van Loy, Cecilia Eydoux, Jean-Claude Guillemot, Etienne Decroly, Federico Gago, Bruno Canard, Maria-Jose Camarasa, Sonsoles Velázquez and Lieve Naesens
Pharmaceuticals 2022, 15(8), 1021; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15081021 - 18 Aug 2022
Cited by 2 | Viewed by 2004
Abstract
There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure–activity relationship of these structurally unique inhibitors. Despite the [...] Read more.
There is a clear need for novel antiviral concepts to control SARS-CoV-2 infection. Based on the promising anti-coronavirus activity observed for a class of 1,4,4-trisubstituted piperidines, we here conducted a detailed analysis of the structure–activity relationship of these structurally unique inhibitors. Despite the presence of five points of diversity, the synthesis of an extensive series of analogues was readily achieved by Ugi four-component reaction from commercially available reagents. After evaluating 63 analogues against human coronavirus 229E, four of the best molecules were selected and shown to have micromolar activity against SARS-CoV-2. Since the action point was situated post virus entry and lying at the stage of viral polyprotein processing and the start of RNA synthesis, enzymatic assays were performed with CoV proteins involved in these processes. While no inhibition was observed for SARS-CoV-2 nsp12-nsp7-nsp8 polymerase, nsp14 N7-methyltransferase and nsp16/nsp10 2’-O-methyltransferase, nor the nsp3 papain-like protease, the compounds clearly inhibited the nsp5 main protease (Mpro). Although the inhibitory activity was quite modest, the plausibility of binding to the catalytic site of Mpro was established by in silico studies. Therefore, the 1,4,4-trisubstituted piperidines appear to represent a novel class of non-covalent CoV Mpro inhibitors that warrants further optimization and development. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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31 pages, 5493 KiB  
Article
Design and Synthesis of Novel Bis-Imidazolyl Phenyl Butadiyne Derivatives as HCV NS5A Inhibitors
by Jehad Hamdy, Nouran Emadeldin, Mostafa M. Hamed, Efseveia Frakolaki, Sotirios Katsamakas, Niki Vassilaki, Grigoris Zoidis, Anna K. H. Hirsch, Mohammad Abdel-Halim and Ashraf H. Abadi
Pharmaceuticals 2022, 15(5), 632; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050632 - 20 May 2022
Cited by 2 | Viewed by 2327
Abstract
In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common [...] Read more.
In today’s global plan to completely eradicate hepatitis C virus (HCV), the essential list of medications used for HCV treatment are direct-acting antivirals (DAAs), as interferon-sparing regimens have become the standard-of-care (SOC) treatment. HCV nonstructural protein 5A (NS5A) inhibitors are a very common component of these regimens. Food and Drug Administration (FDA)-approved NS5A inhibitors, although very potent, do not have the same potency against all eight genotypes of HCV. Therefore, this study aims to synthesize NS5A inhibitor analogues with high potency pan-genotypic activity and high metabolic stability. Starting from an NS5A inhibitor scaffold previously identified by our research group, we made several modifications. Two series of compounds were created to test the effect of changing the length and spatial conformation (para-para vs. meta-meta-positioned bis-imidazole-proline-carbamate), replacing amide groups in the linker with imidazole groups, as well as different end-cap compositions and sizes. The frontrunner inhibits genotype 1b (Con1) replicon, with an EC50 value in the picomolar range, and showed high genotypic coverage with nanomolar range EC50 values against four more genotypes. This together with its high metabolic stability (t½ > 120 min) makes it a potential preclinical candidate. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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16 pages, 2614 KiB  
Article
Methylene Blue Is a Nonspecific Protein–Protein Interaction Inhibitor with Potential for Repurposing as an Antiviral for COVID-19
by Sung-Ting Chuang, Henrietta Papp, Anett Kuczmog, Rebecca Eells, Jose M. Condor Capcha, Lina A. Shehadeh, Ferenc Jakab and Peter Buchwald
Pharmaceuticals 2022, 15(5), 621; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050621 - 18 May 2022
Cited by 8 | Viewed by 4071
Abstract
We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and for other medical applications as a small-molecule inhibitor of the protein–protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, [...] Read more.
We have previously identified methylene blue, a tricyclic phenothiazine dye approved for clinical use for the treatment of methemoglobinemia and for other medical applications as a small-molecule inhibitor of the protein–protein interaction (PPI) between the spike protein of the SARS-CoV-2 coronavirus and ACE2, the first critical step of the attachment and entry of this coronavirus responsible for the COVID-19 pandemic. Here, we show that methylene blue concentration dependently inhibits this PPI for the spike protein of the original strain as well as for those of variants of concern such as the D614G mutant and delta (B.1.617.2) with IC50 in the low micromolar range (1–5 μM). Methylene blue also showed promiscuous activity and inhibited several other PPIs of viral proteins (e.g., HCoV-NL63–ACE2, hepatitis C virus E–CD81) as well as others (e.g., IL-2–IL-2Rα) with similar potency. This nonspecificity notwithstanding, methylene blue inhibited the entry of pseudoviruses bearing the spike protein of SARS-CoV-2 in hACE2-expressing host cells, both for the original strain and the delta variant. It also blocked SARS-CoV-2 (B.1.5) virus replication in Vero E6 cells with an IC50 in the low micromolar range (1.7 μM) when assayed using quantitative PCR of the viral RNA. Thus, while it seems to be a promiscuous PPI inhibitor with low micromolar activity and has a relatively narrow therapeutic index, methylene blue inhibits entry and replication of SARS-CoV-2, including several of its mutant variants, and has potential as a possible inexpensive, broad-spectrum, orally bioactive small-molecule antiviral for the prevention and treatment of COVID-19. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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16 pages, 914 KiB  
Article
Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants
by Océane Delandre, Mathieu Gendrot, Priscilla Jardot, Marion Le Bideau, Manon Boxberger, Céline Boschi, Isabelle Fonta, Joel Mosnier, Sébastien Hutter, Anthony Levasseur, Bernard La Scola and Bruno Pradines
Pharmaceuticals 2022, 15(4), 445; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040445 - 02 Apr 2022
Cited by 6 | Viewed by 7699
Abstract
Over the past two years, several variants of SARS-CoV-2 have emerged and spread all over the world. However, infectivity, clinical severity, re-infection, virulence, transmissibility, vaccine responses and escape, and epidemiological aspects have differed between SARS-CoV-2 variants. Currently, very few treatments are recommended against [...] Read more.
Over the past two years, several variants of SARS-CoV-2 have emerged and spread all over the world. However, infectivity, clinical severity, re-infection, virulence, transmissibility, vaccine responses and escape, and epidemiological aspects have differed between SARS-CoV-2 variants. Currently, very few treatments are recommended against SARS-CoV-2. Identification of effective drugs among repurposing FDA-approved drugs is a rapid, efficient and low-cost strategy against SARS-CoV-2. One of those drugs is ivermectin. Ivermectin is an antihelminthic agent that previously showed in vitro effects against a SARS-CoV-2 isolate (Australia/VI01/2020 isolate) with an IC50 of around 2 µM. We evaluated the in vitro activity of ivermectin on Vero E6 cells infected with 30 clinically isolated SARS-CoV-2 strains belonging to 14 different variants, and particularly 17 strains belonging to six variants of concern (VOC) (variants related to Wuhan, alpha, beta, gamma, delta and omicron). The in vitro activity of ivermectin was compared to those of chloroquine and remdesivir. Unlike chloroquine (EC50 from 4.3 ± 2.5 to 29.3 ± 5.2 µM) or remdesivir (EC50 from 0.4 ± 0.3 to 25.2 ± 9.4 µM), ivermectin showed a relatively homogeneous in vitro activity against SARS-CoV-2 regardless of the strains or variants (EC50 from 5.1 ± 0.5 to 6.7 ± 0.4 µM), except for one omicron strain (EC50 = 1.3 ± 0.5 µM). Ivermectin (No. EC50 = 219, mean EC50 = 5.7 ± 1.0 µM) was, overall, more potent in vitro than chloroquine (No. EC50 = 214, mean EC50 = 16.1 ± 9.0 µM) (p = 1.3 × 10−34) and remdesivir (No. EC50 = 201, mean EC50 = 11.9 ± 10.0 µM) (p = 1.6 × 10−13). These results should be interpreted with caution regarding the potential use of ivermectin in SARS-CoV-2-infected patients: it is difficult to translate in vitro study results into actual clinical treatment in patients. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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13 pages, 852 KiB  
Article
Virological and Immunological Outcomes of an Intensified Four-Drug versus a Standard Three-Drug Antiretroviral Regimen, Both Integrase Strand Transfer Inhibitor-Based, in Primary HIV Infection
by Annalisa Mondi, Carmela Pinnetti, Patrizia Lorenzini, Maria Maddalena Plazzi, Isabella Abbate, Marta Camici, Chiara Agrati, Elisabetta Grilli, Francesca Gili, Rozenn Esvan, Nicoletta Orchi, Gabriella Rozera, Alessandra Amendola, Federica Forbici, Caterina Gori, Roberta Gagliardini, Rita Bellagamba, Adriana Ammassari, Stefania Cicalini, Maria Rosaria Capobianchi and Andrea Antinoriadd Show full author list remove Hide full author list
Pharmaceuticals 2022, 15(4), 403; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040403 - 26 Mar 2022
Cited by 2 | Viewed by 1916
Abstract
The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed [...] Read more.
The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed with PHI from December 2014 to April 2018. Antiretroviral therapy (ART) was started, before genotype resistance test results, with tenofovir/emtricitabine and either raltegravir plus boosted darunavir or dolutegravir. Cumulative probability of virological suppression [VS] (HIV-1 RNA< 40 cp/mL), low-level HIV-1 DNA [LL-HIVDNA] (HIV-1 DNA < 200 copies/106PBMC), and CD4/CD8 ratio ≥1 were estimated using Kaplan–Meier curves. Factors associated with the achievement of VS, LL-HIVDNA, and CD4/CD8 ≥ 1 were assessed by a Cox regression model. We enrolled 144 patients (95.8% male, median age 34 years): 110 (76%) started a four-drug-based therapy, and 34 (24%) a three-drug regimen. Both treatment groups showed a comparable high probability of achieving VS and a similar probability of reaching LL-HIVDNA and a CD4/CD8 ratio ≥1 after 48 weeks from ART initiation. Higher baseline HIV-1 RNA and HIV-1 DNA levels lowered the chance of VS, whereas a better preserved immunocompetence increased that chance. Not statistically significant factors associated with LL-HIVDNA achievement were found, whereas a higher baseline CD4/CD8 ratio predicted the achievement of immune recovery. In PHI patients, the rapid initiation of either an intensified four-drug or a standard three-drug INSTI-based regimen showed comparable responses in terms of VS, viral reservoir size, and immunological recovery. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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12 pages, 1428 KiB  
Article
Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy
by Jessica Cusato, Lucio Boglione, Amedeo De Nicolò, Gian Paolo Caviglia, Simone Mornese Pinna, Alessia Ciancio, Giulia Troshina, Antonina Smedile, Miriam Antonucci, Valeria Avataneo, Alice Palermiti, Jacopo Mula, Alessandra Manca, Giuseppe Cariti, Marco Cantù, Giorgio Maria Saracco, Giovanni Di Perri and Antonio D’Avolio
Pharmaceuticals 2022, 15(3), 355; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15030355 - 15 Mar 2022
Cited by 1 | Viewed by 2441
Abstract
Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained [...] Read more.
Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF–RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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11 pages, 1455 KiB  
Article
Medical-Grade Honey Outperforms Conventional Treatments for Healing Cold Sores—A Clinical Study
by Piyu Parth Naik, Dimitris Mossialos, Bas van Wijk, Petra Novakova, Frank A. D. T. G. Wagener and Niels A. J. Cremers
Pharmaceuticals 2021, 14(12), 1264; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14121264 - 04 Dec 2021
Cited by 5 | Viewed by 15317
Abstract
Cold sores are nasolabial blisters caused by herpes simplex virus (HSV) infections. Novel therapies demonstrating simultaneously antiviral activity and improved wound healing are warranted. The aim of this study was to investigate the efficacy of medical-grade honey (MGH) for treating HSV-induced cold sores. [...] Read more.
Cold sores are nasolabial blisters caused by herpes simplex virus (HSV) infections. Novel therapies demonstrating simultaneously antiviral activity and improved wound healing are warranted. The aim of this study was to investigate the efficacy of medical-grade honey (MGH) for treating HSV-induced cold sores. A crossover trial was performed in patients with recurrent cold sores (n = 29). The majority (65.6%) of these patients experience four or more episodes per year, thus forming a valid self-control group. In this study, patients applied an MGH-based formulation (L-Mesitran Soft) on their cold sore at the onset of symptoms (62.1%) or appearing of blister (37.9%) and compared it to their conventional treatments. After complete healing, patients filled in a questionnaire evaluating healing, pain, and itching. The average absolute healing time was 72.4% slower with conventional treatment (10.0 days) compared to MGH (5.8 days). After MGH treatment, 86.2% of all patients experienced faster objective healing (6.9% similar and 6.9% slower) and the subjective healing score was higher in 79.3% of the patients (20.7% similar). If the patients normally experience pain and itching during their cold sores, these levels were lower with MGH therapy compared to conventional treatment in 72.7% and 71.4% of the patients, respectively. Moreover, 100% of the patients prefer MGH treatment over conventional treatment and will use it again on future cold sores. MGH is a promising alternative treatment for cold sores, likely by combining both increased antiviral and wound healing activities while alleviating pain and itching. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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53 pages, 9378 KiB  
Article
Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4
by Azizah M. Malebari, Shu Wang, Thomas F. Greene, Niamh M. O’Boyle, Darren Fayne, Mohemmed Faraz Khan, Seema M. Nathwani, Brendan Twamley, Thomas McCabe, Daniela M. Zisterer and Mary J. Meegan
Pharmaceuticals 2021, 14(11), 1119; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111119 - 31 Oct 2021
Cited by 8 | Viewed by 3495
Abstract
Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally [...] Read more.
Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound 10n (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound 11n (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC50 values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound 10n demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 10n caused a mitotic catastrophe by targeting tubulin. In addition, compound 10n promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-β-lactams and the amino acid residues of the colchicine binding active site cavity of β-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound 10n, could be promising lead compounds for further clinical anti-cancer drug development. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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11 pages, 1192 KiB  
Communication
Ginkgolic Acid Inhibits Coronavirus Strain 229E Infection of Human Epithelial Lung Cells
by Maimoona S. Bhutta, Daniel G. Sausen, Elisa S. Gallo, Harel Dahari, Gustavo F. Doncel and Ronen Borenstein
Pharmaceuticals 2021, 14(10), 980; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100980 - 26 Sep 2021
Cited by 6 | Viewed by 3262
Abstract
Since December 2019, the COVID-19 pandemic has affected more than 200 million individuals around the globe and caused millions of deaths. Although there are now multiple vaccines for SARS-CoV-2, their efficacy may be limited by current and future viral mutations. Therefore, effective antiviral [...] Read more.
Since December 2019, the COVID-19 pandemic has affected more than 200 million individuals around the globe and caused millions of deaths. Although there are now multiple vaccines for SARS-CoV-2, their efficacy may be limited by current and future viral mutations. Therefore, effective antiviral compounds are an essential component to win the battle against the family of coronaviruses. Ginkgolic Acid (GA) is a pan-antiviral molecule with proven effective in vitro and in vivo activity. We previously demonstrated that GA inhibits Herpes Simplex Virus 1 (HSV-1) by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we reported that GA displays broad-spectrum fusion inhibition encompassing all three classes of fusion proteins, including those of HIV, Ebola, influenza A, and Epstein Barr virus. Here, we report that GA exhibited potent antiviral activity against Human Coronavirus strain 229E (HCoV-229E) infection of human epithelial lung cells (MRC-5). GA significantly reduced progeny virus production, expression of viral proteins, and cytopathic effects (CPE). Furthermore, GA significantly inhibited HCoV-229E even when added post-infection. In light of our findings and the similarities of this family of viruses, GA holds promising potential as an effective antiviral treatment for SARS-CoV-2. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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15 pages, 2191 KiB  
Article
Discovery of a Novel Tetrapeptide against Influenza A Virus: Rational Design, Synthesis, Bioactivity Evaluation and Computational Studies
by Maria Carmina Scala, Mariangela Agamennone, Agostina Pietrantoni, Veronica Di Sarno, Alessia Bertamino, Fabiana Superti, Pietro Campiglia and Marina Sala
Pharmaceuticals 2021, 14(10), 959; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100959 - 23 Sep 2021
Cited by 7 | Viewed by 2356
Abstract
Influenza is a highly contagious, acute respiratory illness, which represents one of the main health issues worldwide. Even though some antivirals are available, the alarming increase in virus strains resistant to them highlights the need to find new drugs. Previously, Superti et al. [...] Read more.
Influenza is a highly contagious, acute respiratory illness, which represents one of the main health issues worldwide. Even though some antivirals are available, the alarming increase in virus strains resistant to them highlights the need to find new drugs. Previously, Superti et al. deeply investigated the mechanism of the anti-influenza virus effect of bovine lactoferrin (bLf) and the role of its tryptic fragments (the N- and C-lobes) in antiviral activity. Recently, through a truncation library, we identified the tetrapeptides, Ac-SKHS-NH2 (1) and Ac-SLDC-NH2 (2), derived from bLf C-lobe fragment 418–429, which were able to bind hemagglutinin (HA) and inhibit cell infection in a concentration range of femto- to picomolar. Starting from these results, in this work, we initiated a systematic SAR study on the peptides mentioned above, through an alanine scanning approach. We carried out binding affinity measurements by microscale thermophoresis (MST) and surface plasmon resonance (SPR), as well as hemagglutination inhibition (HI) and virus neutralization (NT) assays on synthesized peptides. Computational studies were performed to identify possible ligand–HA interactions. Results obtained led to the identification of an interesting peptide endowed with broad anti-influenza activity and able to inhibit viral infection to a greater extent of reference peptide. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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10 pages, 1917 KiB  
Article
Sub-Micromolar Inhibition of SARS-CoV-2 3CLpro by Natural Compounds
by Bruno Rizzuti, Laura Ceballos-Laita, David Ortega-Alarcon, Ana Jimenez-Alesanco, Sonia Vega, Fedora Grande, Filomena Conforti, Olga Abian and Adrian Velazquez-Campoy
Pharmaceuticals 2021, 14(9), 892; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14090892 - 01 Sep 2021
Cited by 17 | Viewed by 4302
Abstract
Inhibiting the main protease 3CLpro is the most common strategy in the search for antiviral drugs to fight the infection from SARS-CoV-2. We report that the natural compound eugenol is able to hamper in vitro the enzymatic activity of 3CLpro, the SARS-CoV-2 main [...] Read more.
Inhibiting the main protease 3CLpro is the most common strategy in the search for antiviral drugs to fight the infection from SARS-CoV-2. We report that the natural compound eugenol is able to hamper in vitro the enzymatic activity of 3CLpro, the SARS-CoV-2 main protease, with an inhibition constant in the sub-micromolar range (Ki = 0.81 μM). Two phenylpropene analogs were also tested: the same effect was observed for estragole with a lower potency (Ki = 4.1 μM), whereas anethole was less active. The binding efficiency index of these compounds is remarkably favorable due also to their small molecular mass (MW < 165 Da). We envision that nanomolar inhibition of 3CLpro is widely accessible within the chemical space of simple natural compounds. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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11 pages, 1998 KiB  
Article
Characterisation of Antiviral Activity of Cathelicidins from Naked Mole Rat and Python bivittatus on Human Herpes Simplex Virus 1
by Alexia Damour, Magali Garcia, Hye-Sun Cho, Andy Larivière, Nicolas Lévêque, Chankyu Park and Charles Bodet
Pharmaceuticals 2021, 14(8), 715; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080715 - 24 Jul 2021
Cited by 2 | Viewed by 2499
Abstract
Hg-CATH and Pb-CATH4 are cathelicidins from Heterocephalus glaber and Python bivittatus that have been previously identified as potent antibacterial peptides. However, their antiviral properties were not previously investigated. In this study, their activity against the herpes simplex virus (HSV)-1 was evaluated during primary [...] Read more.
Hg-CATH and Pb-CATH4 are cathelicidins from Heterocephalus glaber and Python bivittatus that have been previously identified as potent antibacterial peptides. However, their antiviral properties were not previously investigated. In this study, their activity against the herpes simplex virus (HSV)-1 was evaluated during primary human keratinocyte infection. Both of them significantly reduced HSV-1 DNA replication and production of infectious viral particles in keratinocytes at noncytotoxic concentrations, with the stronger activity of Pb-CATH4. These peptides did not show direct virucidal activity and did not exhibit significant immunomodulatory properties, except for Pb-CATH4, which exerted a moderate proinflammatory action. All in all, our results suggest that Hg-CATH and Pb-CATH4 could be potent candidates for the development of new therapies against HSV-1. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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10 pages, 1891 KiB  
Article
Identification of SARS-CoV-2 E Channel Blockers from a Repurposed Drug Library
by Prabhat Pratap Singh Tomar, Miriam Krugliak and Isaiah T. Arkin
Pharmaceuticals 2021, 14(7), 604; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070604 - 23 Jun 2021
Cited by 8 | Viewed by 10233
Abstract
SARS-CoV-2, the etiological agent of the COVID-19 pandemic, is a member of the Coronaviridae family. It is an enveloped virus with ion channels in its membrane, the most characterized of which is the E protein. Therefore, in an attempt to identify blockers of [...] Read more.
SARS-CoV-2, the etiological agent of the COVID-19 pandemic, is a member of the Coronaviridae family. It is an enveloped virus with ion channels in its membrane, the most characterized of which is the E protein. Therefore, in an attempt to identify blockers of the E channel, we screened a library of 2839 approved-for-human-use drugs. Our approach yielded eight compounds that exhibited appreciable activity in three bacteria-based channel assays. Considering the fact that the E channel is the most conserved of all SARS-CoV-2 proteins, any inhibitor of its activity may provide an option to curb the viral spread. In addition, inhibitors can also enhance our ability to understand the exact role played by the E protein during the infectivity cycle. Finally, detailed electrophysiological analyses, alongside in vitro and in vivo studies will be needed to establish the exact potential of each of the blockers identified in our study. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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Review

Jump to: Research

11 pages, 1589 KiB  
Review
Anti-Cytomegalovirus Therapy: Whether and When to Initiate, Those Are the Questions
by Yumi Aoyama, Seiko Sugiyama and Takenobu Yamamoto
Pharmaceuticals 2022, 15(7), 797; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15070797 - 27 Jun 2022
Cited by 1 | Viewed by 1683
Abstract
Cytomegalovirus (CMV) reactivation in patients with autoimmune bullous disease (AIBD) or severe drug eruption treated with immunosuppressive therapy was traditionally thought to be merely an epiphenomenon of the underlying immunosuppression. However, a detailed review of the clinical course of these patients revealed that [...] Read more.
Cytomegalovirus (CMV) reactivation in patients with autoimmune bullous disease (AIBD) or severe drug eruption treated with immunosuppressive therapy was traditionally thought to be merely an epiphenomenon of the underlying immunosuppression. However, a detailed review of the clinical course of these patients revealed that CMV reactivation occurs upon rapid immune recovery, which is termed immune reconstitution inflammatory syndrome (IRIS), and that the timely initiation of anti-CMV therapy, when combined with maintenance doses of immunosuppressive agents, contributes to a rapid resolution of severe infectious complications thought to be refractory to conventional immunosuppressive therapies and unrelated to CMV reactivation. Thus, CMV reactivation resulting in fatal outcomes (CMV-IRIS) can be prevented by the timely detection of CMV DNA or antigens in the blood and by rapidly starting anti-CMV therapy while maintaining immunosuppressive therapy. Anti-CMV therapy is highly recommended for patients with CMV-IRIS or severe drug eruption who have risk factors for CMV reactivation resulting in fatal outcomes. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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32 pages, 2539 KiB  
Review
Lyotropic Liquid Crystalline Nanostructures as Drug Delivery Systems and Vaccine Platforms
by Maria Chountoulesi, Stergios Pispas, Ioulia K. Tseti and Costas Demetzos
Pharmaceuticals 2022, 15(4), 429; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15040429 - 31 Mar 2022
Cited by 24 | Viewed by 7921
Abstract
Lyotropic liquid crystals result from the self-assembly process of amphiphilic molecules, such as lipids, into water, being organized in different mesophases. The non-lamellar formed mesophases, such as bicontinuous cubic (cubosomes) and inverse hexagonal (hexosomes), attract great scientific interest in the field of pharmaceutical [...] Read more.
Lyotropic liquid crystals result from the self-assembly process of amphiphilic molecules, such as lipids, into water, being organized in different mesophases. The non-lamellar formed mesophases, such as bicontinuous cubic (cubosomes) and inverse hexagonal (hexosomes), attract great scientific interest in the field of pharmaceutical nanotechnology. In the present review, an overview of the engineering and characterization of non-lamellar lyotropic liquid crystalline nanosystems (LLCN) is provided, focusing on their advantages as drug delivery nanocarriers and innovative vaccine platforms. It is described that non-lamellar LLCN can be utilized as drug delivery nanosystems, as well as for protein, peptide, and nucleic acid delivery. They exhibit major advantages, including stimuli-responsive properties for the “on demand” drug release delivery and the ability for controlled release by manipulating their internal conformation properties and their administration by different routes. Moreover, non-lamellar LLCN exhibit unique adjuvant properties to activate the immune system, being ideal for the development of novel vaccines. This review outlines the recent advances in lipid-based liquid crystalline technology and highlights the unique features of such systems, with a hopeful scope to contribute to the rational design of future nanosystems. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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26 pages, 7681 KiB  
Review
Antiviral Therapeutic Approaches for SARS-CoV-2 Infection: A Systematic Review
by Victoria Gil Martínez, Ana Avedillo Salas and Sonia Santander Ballestín
Pharmaceuticals 2021, 14(8), 736; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080736 - 28 Jul 2021
Cited by 14 | Viewed by 4084
Abstract
Due to the lack of an etiologic treatment for SARS-CoV-2 and the difficulties involved in developing new drugs, some drugs already approved for other diseases or with efficacy against SARS and MERS, have been used in patients with COVID-19. This systematic review aims [...] Read more.
Due to the lack of an etiologic treatment for SARS-CoV-2 and the difficulties involved in developing new drugs, some drugs already approved for other diseases or with efficacy against SARS and MERS, have been used in patients with COVID-19. This systematic review aims to summarize evidence on the efficacy and safety of five antivirals applied to patients with COVID-19, that have proven to be effective either in vitro studies or in studies on SARS-CoV and MERS.; An intensive search of different databases (Pub Med, WoS, MEDLINE and Cochrane COVID-19 Study Register) has been carried out until the end of April 2021. This systematic review has been conducted according to the PRISMA statement. From each of the included studies, the characteristics of the intervention and comparison groups, demographic data and results were extracted independently; Remdesivir is well tolerated and helps to accelerate clinical improvement but is ineffective in reducing mortality. Favipiravir is safe and shows promising results regarding symptom resolution but does not improve viral clearance. The use of lopinavir/ritonavir has been associated with an increased risk of gastrointestinal adverse events and it has not proven to be effective. No significant differences were observed between patients treated with ribavirin or umifenovir and their respective control groups; Remdesivir and favipiravir are well tolerated and effective in accelerating clinical improvement. This systematic review does not support the use of lopinavir/ritonavir, ribavirin and umifenovir in hospitalized patients with COVID-19. Full article
(This article belongs to the Special Issue Antiviral Drugs 2021)
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