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Special Issue "A Themed Issue Dedicated to Professor Victor Hruby"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Bioorganic Chemistry".

Deadline for manuscript submissions: 28 February 2022.

Special Issue Editors

Prof. Dr. Minying Cai
E-Mail Website1 Website2
Guest Editor
Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
Interests: melanocortin; drug design and discovery; GPCR; peptide and peptidomimetics; pigmentation; melanoma; high throughput screening
Prof. Dr. Paolo Grieco
E-Mail Website
Guest Editor
School of Medicine and Surgery, Department of Pharmacy, Università degli Studi di Napoli Federico II, Naples, Italy
Interests: melanocortin peptides; peptide and peptidomimetic active at urotensin-II receptor; antimicrobial peptides; antiviral peptides

Special Issue Information

Dear Colleagues,

Professor Dr. Victor J. Hruby has for many years been a leader in the design and synthesis of novel peptide and peptidomimetic compounds with novel biological activities. He has designed many peptide and peptidomimetic ligands, particularly of endogenous peptide hormones and neurotransmitters that interact with G-protein coupled receptors (GPCRs), which are involved in virtually all major degenerative and neurodegenerative diseases. Many of these novel ligands have unique biological activity profiles, and thus they have been used for years by many academic and industrial laboratories worldwide for investigating biological functions in relation to health and disease. Many of these compounds have been patented; one of them is on the ethical drug market, and others are being evaluated for their unique treatment potential for a wide variety of degenerative and neurodegenerative diseases and for the prevention and detection of diseases.

Here, I will discuss some of his most important discoveries, most of which have been patented. To begin with, it is important to point out that many of these discoveries were only possible because Dr. Hruby and his students and collaborators also developed many of the technologies and scientific methods that made the discoveries of novel compounds with novel biological activity profiles possible. For example, he was one of the pioneers in the development of nuclear magnetic resonance spectroscopy, and other biophysical methods, to study the conformations and dynamics of peptide hormones and neurotransmitters, their interactions with proteins, and the relationships of these properties to biological activities and functions. This in turn led to the development of conformational constraints via novel designed amino acids, novel cyclization procedures, novel peptidomimetic scaffolds, novel computer aided drug design, and much more, that could be used in the design of novel ligands with novel biological activity profiles. He took his second sabbatical with Martin Karplus when they were developing CHARMM, and later developed a beta site for CHARMM and a macro model for the development of force fields for constrained amino acids and peptides. He was also involved from the very beginning with the discovery of membrane receptors, especially GPCRs, and took his first sabbatical with Marty Rodbell when they were discovering GPCRs, and the assay developments needed to evaluate their signaling and downstream signaling. As a result, he and his group were among the first in the world to have cyclic AMP assays, binding assays, etc., using membranes and later whole cells that had the receptors and other biochemical machinery related to biochemical transduction by hormones and neurotransmitters. As you may know, both Dr. Karplus and Dr. Rodbell later won Nobel prizes in these areas. So Professor Hruby was always a step ahead of most scientists in these areas of science.

In terms of his major discoveries, I will discuss only a select number to illustrate both the depth and breadth of Dr. Hruby's inventiveness. Two very early discoveries still have great significance 30 to 40 years later. He was the first to discover a glucagon antagonist, which is still widely used, and later he discovered the only glucagon inverse agonist, which might have important applications for the treatment of diabetes. A few years later, in the early 1980s, he discovered [Nle4, DPhe7]α-MSH (NDP-MSH), which was the first highly stable peptide hormone derivative. It has been used worldwide as a stable peptide hormone and neurotransmitter peptide derivative in vivo for hundreds of studies of the melanocortin receptor family that have discovered hundreds of biological activities associated with these receptors in health and disease. It is also a drug on the world market, although the patent has expired. It also has unique and very prolonged biological activity in vitro and in vivo. Moreover, Dr. Hruby, in a very clever series of studies, converted somatostatin into the first potent peptide mu opioid receptor antagonist. Again, two of these compounds, CTOP and CTAP, have been used worldwide to this day for many biological studies because of their high selectivity and potency as receptor antagonists and their high stability both in vitro and in vivo. At about the same time, he developed the first highly selective delta opioid receptor agonist based on the natural opioid peptide ligand enkephalin, which is known as DPDPE. This highly selective delta opioid receptor agonist is also very stable in vivo. Since then he has invented and patented many new discoveries in the areas of pain treatment and modulation, including mu and delta receptor bivalent ligands in a single molecule that do not have the toxicities and addiction properties of current opioids and other drugs used in medicine for treating pain. Of particular recent interest are the design of multivalent (di-, tri-, and tetra-valent) peptides and peptidomimetics, which also generally act as agonists at mu and delta opioid receptors in different ratios, and which also act as antagonists of pain-causing receptors that are up regulated in prolonged and neuropathic pain states. These compounds cross the blood–brain barrier and in some cases are orally bioavailable. Collaborations to bring these into clinical medicine are ongoing. At the same time, work on the melanocortin/melanotropin system has been expanded enormously with the discoveries in the 1990s of three additional melanocortin receptors (MC3R, MC4R, and MC5R), which are found throughout the body, and which have as their native peptide hormone and neurotransmitter ligands the melanocyte stimulating hormones derived for POMC (alpha-MSH, beta-MSH, and gamma-MSH). These receptors are found throughout the body and brain and are involved in many diseases including diabetes, obesity, erectile dysfunction, eating disorders, sexual motivation, feeding behavior, stress, immune response, inflammatory response, neurodegenerative diseases, and many others. The Hruby group was the first to develop an antagonist for the MC3R and MC4R (SHU-9119), which has been used worldwide in numerous studies, and has led to the discovery of many biological functions for this system, and for the development in the Hruby group of potential drugs for many applications. These include Alzheimer's disease, stress relief, feeding behavior modulation, sexual behavior and function, mental illness, pigmentary disorders, and others. These novel ligands have been or are being patented and have enormous potential for becoming important medicines for the treatment of many diseases.

Despite the highest levels of success in academics, Dr. Hruby and his colleagues made one of the key discoveries in combinatorial chemistry, namely the Selectide process or the one-bead-one-compound process. This led to a very important patent and the development of a highly successful company, Selectide. Dr. Hruby was a co-inventor on the patent and a co-founder of the company. Currently, he has two invented drugs that have been approved by the FDA and several others approved in Europe and Australia.

Although Professor Hruby has not yet received a Nobel Prize, his impact in the peptide science field for novel drug design and discovery is superior to many laureates.

Prof. Dr. Minying Cai
Prof. Dr. Paolo Grieco
Guest Editors

Manuscript Submission Information

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Keywords

  • structure–activity relationships
  • drug design of ligands
  • conformational studies
  • biological activity
  • pharmacology
  • drug delivery
  • obesity
  • inflammation
  • melanoma
  • erectile dysfunction

Published Papers (7 papers)

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Research

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Article
Aged Brains Express Less Melanocortin Receptors, Which Correlates with Age-Related Decline of Cognitive Functions
Molecules 2021, 26(20), 6266; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26206266 - 16 Oct 2021
Viewed by 433
Abstract
Brain G-protein coupled receptors have been hypothesized to be potential targets for maintaining or restoring cognitive function in normal aged individuals or in patients with neurodegenerative disease. A number of recent reports suggest that activation of melanocortin receptors (MCRs) in the brain can [...] Read more.
Brain G-protein coupled receptors have been hypothesized to be potential targets for maintaining or restoring cognitive function in normal aged individuals or in patients with neurodegenerative disease. A number of recent reports suggest that activation of melanocortin receptors (MCRs) in the brain can significantly improve cognitive functions of normal rodents and of different rodent models of the Alzheimer’s disease. However, the potential impact of normative aging on the expression of MCRs and their potential roles for modulating cognitive function remains to be elucidated. In the present study, we first investigated the expression of these receptors in six different brain regions of young (6 months) and aged (23 months) rats following assessment of their cognitive status. Correlation analysis was further performed to reveal potential contributions of MCR subtypes to spatial learning and memory. Our results revealed statistically significant correlations between the expression of several MCR subtypes in the frontal cortex/hypothalamus and the hippocampus regions and the rats’ performance in spatial learning and memory only in the aged rats. These findings support the hypothesis that aging has a direct impact on the expression and function of MCRs, establishing MCRs as potential drug targets to alleviate aging-induced decline of cognitive function. Full article
(This article belongs to the Special Issue A Themed Issue Dedicated to Professor Victor Hruby)
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Article
Enabling Efficient Folding and High-Resolution Crystallographic Analysis of Bracelet Cyclotides
Molecules 2021, 26(18), 5554; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185554 - 13 Sep 2021
Cited by 1 | Viewed by 593
Abstract
Cyclotides have attracted great interest as drug design scaffolds because of their unique cyclic cystine knotted topology. They are classified into three subfamilies, among which the bracelet subfamily represents the majority and comprises the most bioactive cyclotides, but are the most poorly utilized [...] Read more.
Cyclotides have attracted great interest as drug design scaffolds because of their unique cyclic cystine knotted topology. They are classified into three subfamilies, among which the bracelet subfamily represents the majority and comprises the most bioactive cyclotides, but are the most poorly utilized in drug design applications. A long-standing challenge has been the very low in vitro folding yields of bracelets, hampering efforts to characterize their structures and activities. Herein, we report substantial increases in bracelet folding yields enabled by a single point mutation of residue Ile-11 to Leu or Gly. We applied this discovery to synthesize mirror image enantiomers and used quasi-racemic crystallography to elucidate the first crystal structures of bracelet cyclotides. This study provides a facile strategy to produce bracelet cyclotides, leading to a general method to easily access their atomic resolution structures and providing a basis for development of biotechnological applications. Full article
(This article belongs to the Special Issue A Themed Issue Dedicated to Professor Victor Hruby)
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Article
Harnessing the Anti-Nociceptive Potential of NK2 and NK3 Ligands in the Design of New Multifunctional μ/δ-Opioid Agonist–Neurokinin Antagonist Peptidomimetics
Molecules 2021, 26(17), 5406; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26175406 - 06 Sep 2021
Viewed by 611
Abstract
Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a [...] Read more.
Opioid agonists are well-established analgesics, widely prescribed for acute but also chronic pain. However, their efficiency comes with the price of drastically impacting side effects that are inherently linked to their prolonged use. To answer these liabilities, designed multiple ligands (DMLs) offer a promising strategy by co-targeting opioid and non-opioid signaling pathways involved in nociception. Despite being intimately linked to the Substance P (SP)/neurokinin 1 (NK1) system, which is broadly examined for pain treatment, the neurokinin receptors NK2 and NK3 have so far been neglected in such DMLs. Herein, a series of newly designed opioid agonist-NK2 or -NK3 antagonists is reported. A selection of reported peptidic, pseudo-peptidic, and non-peptide neurokinin NK2 and NK3 ligands were covalently linked to the peptidic μ-opioid selective pharmacophore Dmt-DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) and the dual μ/δ opioid agonist H-Dmt-d-Arg-Aba-βAla-NH2 (KGOP01). Opioid binding assays unequivocally demonstrated that only hybrids SBL-OPNK-5, SBL-OPNK-7 and SBL-OPNK-9, bearing the KGOP01 scaffold, conserved nanomolar range μ-opioid receptor (MOR) affinity, and slightly reduced affinity for the δ-opioid receptor (DOR). Moreover, NK binding experiments proved that compounds SBL-OPNK-5, SBL-OPNK-7, and SBL-OPNK-9 exhibited (sub)nanomolar binding affinity for NK2 and NK3, opening promising opportunities for the design of next-generation opioid hybrids. Full article
(This article belongs to the Special Issue A Themed Issue Dedicated to Professor Victor Hruby)
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Article
Synthesis and In Vitro Characterization of Glycopeptide Drug Candidates Related to PACAP1–23
Molecules 2021, 26(16), 4932; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26164932 - 14 Aug 2021
Cited by 1 | Viewed by 811
Abstract
The search for efficacious treatment of neurodegenerative and progressive neuroinflammatory diseases continues, as current therapies are unable to halt or reverse disease progression. PACAP represents one potential therapeutic that provides neuroprotection effects on neurons, and also modulates inflammatory responses and circulation within the [...] Read more.
The search for efficacious treatment of neurodegenerative and progressive neuroinflammatory diseases continues, as current therapies are unable to halt or reverse disease progression. PACAP represents one potential therapeutic that provides neuroprotection effects on neurons, and also modulates inflammatory responses and circulation within the brain. However, PACAP is a relatively long peptide hormone that is not trivial to synthesize. Based on previous observations that the shortened isoform PACAP1–23 is capable of inducing neuroprotection in vitro, we were inspired to synthesize shortened glycopeptide analogues of PACAP1–23. Herein, we report the synthesis and in vitro characterization of glycosylated PACAP1–23 analogues that interact strongly with the PAC1 and VPAC1 receptors, while showing reduced activity at the VPAC2 receptor. Full article
(This article belongs to the Special Issue A Themed Issue Dedicated to Professor Victor Hruby)
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Article
Facile Synthesis of 2H-Benzo[h]Chromenes via an Arylamine-Catalyzed Mannich Cyclization Cascade Reaction
Molecules 2021, 26(12), 3617; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26123617 - 12 Jun 2021
Cited by 1 | Viewed by 743
Abstract
A simple arylamine-catalyzed Mannich-cyclization cascade reaction was developed for facile synthesis of substituted 2H-benzo[h]chromenes. The notable feature of the process included the efficient generation of ortho-quinone methides (o-QMs) catalyzed by a simple aniline. The mild reaction [...] Read more.
A simple arylamine-catalyzed Mannich-cyclization cascade reaction was developed for facile synthesis of substituted 2H-benzo[h]chromenes. The notable feature of the process included the efficient generation of ortho-quinone methides (o-QMs) catalyzed by a simple aniline. The mild reaction conditions allowed for a broad spectrum of 1- and 2-naphthols and trans-cinnamaldehydes to engage in the cascade sequence with high efficiency. Full article
(This article belongs to the Special Issue A Themed Issue Dedicated to Professor Victor Hruby)
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Review

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Review
Natural and Synthetic Halogenated Amino Acids—Structural and Bioactive Features in Antimicrobial Peptides and Peptidomimetics
Molecules 2021, 26(23), 7401; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26237401 - 06 Dec 2021
Viewed by 480
Abstract
The 3D structure and surface characteristics of proteins and peptides are crucial for interactions with receptors or ligands and can be modified to some extent to modulate their biological roles and pharmacological activities. The introduction of halogen atoms on the side-chains of amino [...] Read more.
The 3D structure and surface characteristics of proteins and peptides are crucial for interactions with receptors or ligands and can be modified to some extent to modulate their biological roles and pharmacological activities. The introduction of halogen atoms on the side-chains of amino acids is a powerful tool for effecting this type of tuning, influencing both the physico-chemical and structural properties of the modified polypeptides, helping to first dissect and then rationally modify features that affect their mode of action. This review provides examples of the influence of different types of halogenation in amino acids that replace native residues in proteins and peptides. Examples of synthetic strategies for obtaining halogenated amino acids are also provided, focusing on some representative compounds and their biological effects. The role of halogenation in native and designed antimicrobial peptides (AMPs) and their mimetics is then discussed. These are in the spotlight for the development of new antimicrobial drugs to counter the rise of antibiotic-resistant pathogens. AMPs represent an interesting model to study the role that natural halogenation has on their mode of action and also to understand how artificially halogenated residues can be used to rationally modify and optimize AMPs for pharmaceutical purposes. Full article
(This article belongs to the Special Issue A Themed Issue Dedicated to Professor Victor Hruby)
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Review
Plasmon Waveguide Resonance: Principles, Applications and Historical Perspectives on Instrument Development
Molecules 2021, 26(21), 6442; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216442 - 26 Oct 2021
Viewed by 532
Abstract
Plasmon waveguide resonance (PWR) is a variant of surface plasmon resonance (SPR) that was invented about two decades ago at the University of Arizona. In addition to the characterization of the kinetics and affinity of molecular interactions, PWR possesses several advantages relative to [...] Read more.
Plasmon waveguide resonance (PWR) is a variant of surface plasmon resonance (SPR) that was invented about two decades ago at the University of Arizona. In addition to the characterization of the kinetics and affinity of molecular interactions, PWR possesses several advantages relative to SPR, namely, the ability to monitor both mass and structural changes. PWR allows anisotropy information to be obtained and is ideal for the investigation of molecular interactions occurring in anisotropic-oriented thin films. In this review, we will revisit main PWR applications, aiming at characterizing molecular interactions occurring (1) at lipid membranes deposited in the sensor and (2) in chemically modified sensors. Among the most widely used applications is the investigation of G-protein coupled receptor (GPCR) ligand activation and the study of the lipid environment’s impact on this process. Pioneering PWR studies on GPCRs were carried out thanks to the strong and effective collaboration between two laboratories in the University of Arizona leaded by Dr. Gordon Tollin and Dr. Victor J. Hruby. This review provides an overview of the main applications of PWR and provides a historical perspective on the development of instruments since the first prototype and continuous technological improvements to ongoing and future developments, aiming at broadening the information obtained and expanding the application portfolio. Full article
(This article belongs to the Special Issue A Themed Issue Dedicated to Professor Victor Hruby)
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