A Themed Issue Dedicated to Professor Victor Hruby

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

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