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Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 14035

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Dr. Panagiotis Mallis

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Department of Tissue Engineering and Regenerative Medicine of Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens (BRFAA), 11527 Athina, Greece
Interests: immunobiology of stem cells; molecular genetics of HLA; tissue-engineered small-diameter vascular grafts; immunobiology of biological scaffolds; mesenchymal stromal cells; hematopoietic stem cells biology
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Dr. Efstathios Michalopoulos

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Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, Greece
Interests: tissue engineering; regenerative medicine; mesenchymal stromal cells; hematopoietic stem cells; vascular grafts; immunobiology; platelet gel
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Prof. Dr. Catherine Stavropoulos-Giokas

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Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 4 Soranou Ephessiou Street, 11527 Athens, Greece
Interests: tissue engineering; vascular tissue; vascular grafting; articular cartilage; stem cells

Special Issue Information

Dear Colleagues,

The topic of this Special Issue concerns the utilization of “Advanced Therapy Medicinal Products (ATMPs)” for the better treatment of immune dysregulation disorders, including COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for COVID-19, which started in December 2019. Clinical manifestations of SARS-CoV-2 include the direct injury of infected target cells, which can further extend into circulatory dysfunction, damage lung alveolar epithelial cells, and cause acute respiratory distress syndrome (ARDS), the latter of which tends to be the initial reason for a multitude of patients being hospitalized in intensive care units (ICUs), with the disease proving to be life-threatening for severe COVID-19 patients. On the other hand, the pathogenetic mechanism of SARS-CoV-2 has not been fully revealed and is currently under investigation by many different research groups worldwide. The thus far published data indicate that SARS-CoV-2 is responsible for the induction of immunopathological defects occurring mostly through its escape from pattern recognition receptors (PRRs) of innate immunity cells, the dysregulation of macrophage function (M1 phenotype adaptation), overstimulation of CD4+ and CD8+ T cells and B cells, and, lastly, the overproduction of inflammatory cytokines (such as IL-1, IL-2, IL-6, IL-7, G-CSF, IP10, MCP1, MIP1A, and TNF-α), a situation known as cytokine release syndrome or “cytokine storm”. Furthermore, critically ill COVID-19 patients exhibit extended lymphopenia, thrombocytopenia, abnormal immune responses, and multiorgan failure (e.g., heart, liver, kidney, and lung fibrosis).

Recently, besides the already established therapeutic protocols, ATMPs have also been considered as candidates for a therapeutic approach, especially for severely ill COVID-19 patients admitted to ICUs. ATMPs involve the utilization of mesenchymal stromal cells (MSCs; with known immunoregulatory/immunomodulatory properties) and chimeric antigen receptor (CAR) T and NK cells, which may also be considered as potential candidates. To date, the US Food and Drug Administration (FDA) has granted clearance for the performance of phase I/II clinical trials for investigational COVID-19 therapy utilizing allogeneic MSCs.

Considering that the pathological mechanism of COVID-19 is actually very similar to other immune-related disorders, data obtained from future research may not be limited to this disease, but could possibly be utilized in other disorders such as autoimmune diseases.

We are glad to present the Special Issue entitled “ Advanced Therapeutic Medicinal Products as Potential Therapeutic Strategy Against COVID-19 and Immune-Related Disorders”. This collection of articles aims to include original research articles, opinion articles, and comprehensive reviews related to state-of-the-art ATMP research.

We look forward to your submissions.

Dr. Panagiotis Mallis
Dr. Efstathios Michalopoulos
Prof. Dr. Catherine Stavropoulos-Giokas
Guest Editors

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Published Papers (7 papers)

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Editorial

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4 pages, 181 KiB

Open AccessEditorial

Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders

by Panagiotis Mallis, Efstathios Michalopoulos and Catherine Stavropoulos-Giokas

Int. J. Mol. Sci. 2024, 25(5), 3079; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25053079 - 06 Mar 2024

Viewed by 704

Abstract

Advanced Therapy Medicinal Products (ATMPs) comprise a heterogenous class of innovative medicinal products, which further require extensive preclinical and clinical assessments before their broader use in the general population [...] Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders)

Research

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18 pages, 3619 KiB

Open AccessArticle

Specific Activation of T Cells by an ACE2-Based CAR-Like Receptor upon Recognition of SARS-CoV-2 Spike Protein

by Pablo Gonzalez-Garcia, Juan P. Muñoz-Miranda, Ricardo Fernandez-Cisnal, Lucia Olvera, Noelia Moares, Antonio Gabucio, Cecilia Fernandez-Ponce and Francisco Garcia-Cozar

Int. J. Mol. Sci. 2023, 24(8), 7641; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087641 - 21 Apr 2023

Cited by 4 | Viewed by 1931

Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of the Coronavirus Disease 2019 (COVID-19) pandemic, which is still a health issue worldwide mostly due to a high rate of contagiousness conferred by the high-affinity binding between cell viral receptors, Angiotensin-Converting Enzyme 2 (ACE2) and SARS-CoV-2 Spike protein. Therapies have been developed that rely on the use of antibodies or the induction of their production (vaccination), but despite vaccination being still largely protective, the efficacy of antibody-based therapies wanes with the advent of new viral variants. Chimeric Antigen Receptor (CAR) therapy has shown promise for tumors and has also been proposed for COVID-19 treatment, but as recognition of CARs still relies on antibody-derived sequences, they will still be hampered by the high evasion capacity of the virus. In this manuscript, we show the results from CAR-like constructs with a recognition domain based on the ACE2 viral receptor, whose ability to bind the virus will not wane, as Spike/ACE2 interaction is pivotal for viral entry. Moreover, we have developed a CAR construct based on an affinity-optimized ACE2 and showed that both wild-type and affinity-optimized ACE2 CARs drive activation of a T cell line in response to SARS-CoV-2 Spike protein expressed on a pulmonary cell line. Our work sets the stage for the development of CAR-like constructs against infectious agents that would not be affected by viral escape mutations and could be developed as soon as the receptor is identified. Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders)

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17 pages, 21053 KiB

Open AccessArticle

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

by Sakshi Piplani, Puneet Singh, Nikolai Petrovsky and David A. Winkler

Int. J. Mol. Sci. 2023, 24(4), 4192; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24044192 - 20 Feb 2023

Cited by 4 | Viewed by 2054

Abstract

Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery. Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders)

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19 pages, 7707 KiB

Open AccessArticle

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies

by Assem Barakat, Ahmed Mostafa, M. Ali, Abdullah Mohammed Al-Majid, Luis R. Domingo, Omnia Kutkat, Yassmin Moatasim, Komal Zia, Zaheer Ul-Haq and Yaseen A. M. M. Elshaier

Int. J. Mol. Sci. 2022, 23(19), 11861; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911861 - 06 Oct 2022

Cited by 7 | Viewed by 2072

Abstract

The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC₅₀ values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC₅₀ against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC₅₀ values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC₅₀ = 3.275 µM and half maximal cytotoxic-concentration CC₅₀ = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol. Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders)

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17 pages, 4758 KiB

Open AccessArticle

Cheminformatics-Based Discovery of Potential Chemical Probe Inhibitors of Omicron Spike Protein

by Salman Ali Khan, Alamgir Khan, Komal Zia, Ihab Shawish, Assem Barakat and Zaheer Ul-Haq

Int. J. Mol. Sci. 2022, 23(18), 10315; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810315 - 07 Sep 2022

Cited by 7 | Viewed by 1684

Abstract

During the past two decades, the world has witnessed the emergence of various SARS-CoV-2 variants with distinct mutational profiles influencing the global health, economy, and clinical aspects of the COVID-19 pandemic. These variants or mutants have raised major concerns regarding the protection provided by neutralizing monoclonal antibodies and vaccination, rates of virus transmission, and/or the risk of reinfection. The newly emerged Omicron, a genetically distinct lineage of SARS-CoV-2, continues its spread in the face of rising vaccine-induced immunity while maintaining its replication fitness. Efforts have been made to improve the therapeutic interventions and the FDA has issued Emergency Use Authorization for a few monoclonal antibodies and drug treatments for COVID-19. However, the current situation of rapidly spreading Omicron and its lineages demands the need for effective therapeutic interventions to reduce the COVID-19 pandemic. Several experimental studies have indicated that the FDA-approved monoclonal antibodies are less effective than antiviral drugs against the Omicron variant. Thus, in this study, we aim to identify antiviral compounds against the Spike protein of Omicron, which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor and facilitates virus invasion. Initially, docking-based virtual screening of the in-house database was performed to extract the potential hit compounds against the Spike protein. The obtained hits were optimized by DFT calculations to determine the electronic properties and molecular reactivity of the compounds. Further, MD simulation studies were carried out to evaluate the dynamics of protein–ligand interactions at an atomistic level in a time-dependent manner. Collectively, five compounds (AKS-01, AKS-02, AKS-03, AKS-04, and AKS-05) with diverse scaffolds were identified as potential hits against the Spike protein of Omicron. Our study paves the way for further in vitro and in vivo studies. Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders)

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Review

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24 pages, 1013 KiB

Open AccessReview

Antigen-Specific T Cells and SARS-CoV-2 Infection: Current Approaches and Future Possibilities

by Zuzana Nova, Tomas Zemanek and Norbert Botek

Int. J. Mol. Sci. 2022, 23(23), 15122; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315122 - 01 Dec 2022

Cited by 1 | Viewed by 1553

Abstract

COVID-19, a significant global health threat, appears to be an immune-related disease. Failure of effective immune responses in initial stages of infection may contribute to development of cytokine storm and systemic inflammation with organ damage, leading to poor clinical outcomes. Disease severity and the emergence of new SARS-CoV-2 variants highlight the need for new preventative and therapeutic strategies to protect the immunocompromised population. Available data indicate that these people may benefit from adoptive transfer of allogeneic SARS-CoV-2-specific T cells isolated from convalescent individuals. This review first provides an insight into the mechanism of cytokine storm development, as it is directly related to the exhaustion of T cell population, essential for viral clearance and long-term antiviral immunity. Next, we describe virus-specific T lymphocytes as a promising and efficient approach for the treatment and prevention of severe COVID-19. Furthermore, other potential cell-based therapies, including natural killer cells, regulatory T cells and mesenchymal stem cells are mentioned. Additionally, we discuss fast and effective ways of producing clinical-grade antigen-specific T cells which can be cryopreserved and serve as an effective “off-the-shelf” approach for rapid treatment of SARS-CoV-2 infection in case of sudden patient deterioration. Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders)

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23 pages, 1863 KiB

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COVID-19 Molecular Pathophysiology: Acetylation of Repurposing Drugs

by Jong Hoon Lee, Badar Kanwar, Asif Khattak, Jenny Balentine, Ngoc Huy Nguyen, Richard E. Kast, Chul Joong Lee, Jean Bourbeau, Eric L. Altschuler, Consolato M. Sergi, Tuan Ngoc Minh Nguyen, Sangsuk Oh, Mun-Gi Sohn and Michael Coleman

Int. J. Mol. Sci. 2022, 23(21), 13260; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113260 - 31 Oct 2022

Cited by 7 | Viewed by 3227

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated type 1 interferon (IFN-1) production, the pathophysiology of which involves sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) tetramerization and the cytosolic DNA sensor cyclic-GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling pathway. As a result, type I interferonopathies are exacerbated. Aspirin inhibits cGAS-mediated signaling through cGAS acetylation. Acetylation contributes to cGAS activity control and activates IFN-1 production and nuclear factor-κB (NF-κB) signaling via STING. Aspirin and dapsone inhibit the activation of both IFN-1 and NF-κB by targeting cGAS. We define these as anticatalytic mechanisms. It is necessary to alleviate the pathologic course and take the lag time of the odds of achieving viral clearance by day 7 to coordinate innate or adaptive immune cell reactions. Full article

(This article belongs to the Special Issue Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders)

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Advanced Therapy Medicinal Products as Potential Therapeutic Strategy against COVID-19 and Immune-Related Disorders

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