VICTOR J. HRUBY
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    Telephone: (520) 621-6332
    FAX: (520) 621-8407
    hruby@u.arizona.edu

  • Organic Chemistry, Biochemistry and Medicinal Chemistry

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

    1. Asymmetric synthesis of topographically controlled amino acids and their derivatives including the following:

    2. Glucagon-mechanisms of hormone action and relationship to diabetes; antagonist design.

    Glucagon has been implicated (along with insulin) as an important factor in diabetes. We are developing glucagon antagonists that block the effects of glucagon at membrane receptors and in diabetic animals.

    3. Synthesis and conformation-activity relationships of alpha-melanotropin (alpha-MSH) in relation to melanoma cancer, pigmentation, feeding behavior, cardiovascular function, renal function and learning.

    We have developed conformationally restricted alpha-MSH analogs 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, more potent and selective compounds including agonists and antagonists for several new melanocortin receptors.

    4. Design and synthesis of conformationally constrained neuropeptides. Conformationally restricted, cyclic, rigid enkephalin, deltorphin, somatostatin, cholecystokinin and dynorphin analogs with high receptor specificity are being developed. The conformational basis for their selectivity is being investigated as are new analogs 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.

    5. Conformationally constrained oxytocin and vasopressin agonists and antagonists: conformation-biological activity relationships and peptide mimetic design.

    Design, synthesis and conformational analysis of peptide analogs that can be used to study premature birth, satiety and behavior.


    Selected Publications



    "Diasterospecific Tandem Michael-Like Add-ition/Electrophilic Bromination: A One Pot Tan-dem Asymmetric Synthesis of Precursors of Un-usual Amino Acids," G. Li, M.A. Jarosinski & V.J. Hruby, Tet. Letters, 34, 2561 (1993).

    "X-Ray Structure of [D-Pen2,D-Pen5]Enkephalin, A Highly Potent, Delta Opioid Receptor Selective Compound: Comparisons With Proposed Solution Conformations," J.L. Flippen-Anderson, V.J. Hruby, N. Collins, C. George & B. Cudney, J. Am. Chem. Soc., 116, 7523 (1994).

    "Cyclic Lactam -Melanotropin Analogues of Ac-Nle4-c[Asp5,D-Phe7,Lys10]-MSH(4-10)-NH2 with Bulky Aromatic Amino Acids at Position 7 Show High Antagonist Potency and Selectivity at Specific Melanocortin Receptors," V.J. Hruby, D. Lu, S.D. Sharma, A. de L. Castrucci, R.A. Kesterson, F.A. Al-Obeidi, M.E. Hadley, & R.D. Cone, J. Med. Chem., 38, 3454-3461 (1995).

    "Low Level Cyclic Adenosine 3',5'-Monophosphate Accumulation Analysis of [desHis1, desPhe6,Glu9]-Glucagon-NH2 Identifies Glucagon Antagonists from Weak Partial Agonists/-Antagonists," B.A. Van Tine, B.Y. Azizeh, D. Trivedi, J.R. Phelps, M.D. Houslay, D.G. Johnson & V.J. Hruby, Endocrinology, 137, 3316-3322 (1996).

    "Probing the Stereochemical Requirements for Receptor Recognition of Opioid Agonists Through Topographic Modifications in Position 1," X. Qian, M.D. Shenderovich, K.E. Kövér, P. Davis, R. Horváth, T. Zalewska, H.I. Yamamura, F. Porreca & V.J. Hruby, J. Am. Chem. Soc., 118, 7280-7290 (1996).

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