Victor J. Hruby

Regents' Professor

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Research Interests

Our research group is interested in the design, synthesis, analysis, conformations, dynamics and structure-biological activity relationships of biologically active peptides and peptide mimetics with special interests in hormones and neurotransmitters that affect human behavior. We are interested in the rational design of antihormones (inhibitors) based on conformation, in hormone and neurotransmitter receptors, in brain chemistry, in the design and asymmetric synthesis of conformationally constrained amino acids, peptides and peptide mimetics, and in the use of NMR and other physical methods to examine peptide and peptidomimetic conformations. We seek to understand the physical-chemical basis for information transfer for these important molecules in biological systems, and utilize synthetic organic chemistry, structural chemistry, bio-organic chemistry, analytical chemistry, physical chemistry, and biology to examine the relationships of structure to information transduction. Some projects include:

1. Asymmetric synthesis of topographically controlled amino acids and their derivatives and β-turn mimetics, including the following:

2. Synthesis and conformation-bioactivity relationships of alpha-melanotropin (alpha-MSH) in relation to melanoma cancer, pigmentation, feeding behavior, sexual behavior,  cardiovascular function, renal function, pain, and learning.  We have developed conformationally restricted alpha-MSH analogues with extraordinary in vitro and in vivo biological properties including superpotency, superagonist activity, superantagonist activity and super prolonged activity. Computer assisted modeling is being used for design of new scaffolds and more potent and selective compounds including agonists and antagonists for several new melanocortin receptors.

3. Design and synthesis of conformationally constrained neuropeptides. Conformationally restricted, cyclic, rigid enkephalin, deltorphin, somatostatin, cholecystokinin and dynorphin analogues with high receptor specificity and novel bioactivity profiles are being developed. Using a new design principle we are examining the design of ligands that can treat disease states (e.g. neuropathic pain) by design of ligands with overlapping pharmacophores that can simultaneously interact at different receptor types and with different pharmacologies. The conformational basis for their selectivity is being investigated as are new analogues that will modulate pain, behavior, learning, memory, satiety and other CNS effects, and for treatment of AIDS. This information is used in de novo peptidomimetic design.

4. Conformationally constrained oxytocin and vasopressin agonists and antagonists:
conformation-biological activity relationships and peptide mimetic design. Design, synthesis and conformational analysis of peptide analogues that can be used to study premature birth, satiety and behavior.

5. We are designing multimeric ligands that can act as molecular machines that will recognize the surface of cancer cells, but not of normal cells, for use in medical diagnosis of cancer, molecular imaging, and cancer therapeutics.

Selected Publications

Juni A, Cai M, Stankova M, Waxman AR, Arout C, Klein G, Dahan A, Hruby VJ, Mogil JS, Kest B. Jan 2010. Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor. Anesthesiology, 112:181-8

De Silva CR, Vagner J, Lynch R, Gillies RJ, Hruby VJ. Mar 2010. Optimazation of time-resolved fluorescence assay for detectin of europium-tetraazacyclododecyltetraacetic acid-labeled ligand-receptor interactions. Anal Biochem, 398:15-23

Vagner J, Qu H, Hruby VJ. Jun 2009. Peptidomimetics, a synthetic tool of drug discovery. Curr Opin Chem Biol, 12:292-6

Nair P, Yamamoto T, Kulkarni V, Moye S, Navratilova E, David P, Largent T, Ma SW, Yamamura HI, Vanderah T, Lai J, Porreca F, Hruby VJ. Oct 2009. Novel bifunctional peptides as opioid agonists and NK-1 antagonists. Adv Exp Med Biol, 611:537-8