Victor J Hruby, PhD

Regents Professor of Chemistry
Email Address: 
Phone Number: 
(520)-621-6332
FAX: 
(520)-621-8407
Professional Bio: 

During the past 45+ years Dr. Hruby and his group have been developing a multidisciplinary approach to the study of peptide hormones and neurotransmitters and their receptors (mostly GPCRs), which has as its major goal developing an understanding of the chemical/physical basis for their effects on human health and disease. This research has involved close collaboration with biologists and medical doctors. They seek to develop peptide and peptidomimetic agonist, antagonist, and inverse agonist ligands that are conformationally constrained and stable in biological environments, can cross (or not) membrane barriers including the blood brain barrier and have unique biological profiles in vivo. They have been highly successful and developed state-of-the-art peptide and peptidomimetic synthesis; asymmetric synthesis of novel chi constrained amino acids, β-turn mimetics, etc. and their chimeric derivatives; computational chemistry and molecular modeling including binding to GPCRs of interest; development of state-of-the-art NMR methods to study peptide and peptidomimetic conformations in solution and in membrane environments, and conformations when interacting (binding) to their receptors.

They have developed selective and biologically stable agonists and antagonists for use in biological systems including oxytocin agonist and antagonist ligands that are potent and selective for peripheral and brain receptors, melanotropin agonist and antagonist analogues for the melanocortin 1, 3, 4 and 5 receptors, and novel cyclic and constrained ligands that are potent and selective analogues for the mu, delta or kappa opioid receptors, ligands that are potent and selective for bradykinin receptors, and cholecystokinin receptors, and multivalent ligands of various compositions and structural types. With biological and medical colleagues we have demonstrated in vivo biological activities in health and disease related to maternal behavior, learning behavior, sexual behavior, including psychogenic erectile dysfunction, feeding behavior including obesity and anorexia, immune response, pigmentary response including melanoma cancer and cancer prevention, pain including prolonged and neuropathic pain, etc. With our medical colleagues we have done several clinical trials, and are prepared to do more when given the opportunity.

Clinical Information

Clinical Focus: 

Disease or Clinical Specialty: 
Dermatology
Melanoma
Nonmelanoma Skin Cancer

Research Information

Research Program: 
Therapeutic Development
Member Status: 
Research Member
Selected Publications: 
  1. Sawyer, T.K.,Sanfilippo, P.J., Hruby, V.J., Engel, M.H., Heward, C.B., Burnett, J.B., and Hadley, M.E., [Nle4, D-Phe7]-α-Melanocyte Stimulating Hormone: A Highly Potent α-Melanotropin with Ultralong Biological Activity, Proc. Natl. Acad. Sci. U.S.A., 77, 5754-5758 (1980).
  2. Al-Obeidi, F., Hadley, M.E., Pettitt, B.M.and Hruby, V.J., Design of a New Class of Superpotent Cyclic α-Melanotropins Based on Quenched Dynamic Simulations, J. Amer. Chem. Soc., 111, 3413-3416 (1989).
  3. Fan W., Boston, B.A., Kesterson, R.A., Hruby, V.J. and Cone, R.D., Role of Melanocortinergic Neurons in Feeding and the Agouti Obesity Syndrome, Nature, 385, 165-168 (1997).
  4. Hruby, V.J., Designing Peptide Receptor Agonists and Antagonists, Nature Reviews Drug Discovery, 1, 847-858 (2002).
  5. Mosberg, H.I., Hurst, R., Hruby, V.J., Gee, K., Yamamura, H.I., Galligan, J.J. and Burks, T.F., Bis-Penicillamine Enkephalins Possess Highly Improved Specificity Toward Delta Opioid Receptors, Proc. Natl. Acad. Sci. U.S.A., 80, 5871-5874 (1983).
  6. Hruby, V.J. Hruby, Kao, L-F., Pettitt, B.M. and Karplus, M., The Conformational Properties of the Delta Opioid Peptide [D-Pen2, D-Pen5]-enkephalin in Aqueous Solution Determined by NMR and Energy Minimization Calculations, J. Am. Chem. Soc., 110, 3351-3359 (1988).
  7. Cai, M., Nyberg, J. and Hruby, V.J., Melanotropins as Drugs for the Treatment of Obesity and Other Feeding Disorders: Potential and Problems, Curr. Topics Med. Chem., 9, 554-563 (2009).
  8. Flippen-Anderson, J.L., Hruby, V.J., Collins,N., George, C. and Cudney, B., X-Ray Structure of [D-Pen2, D-Pen5]Enkephalin, A Highly Potent, Delta Opioid Receptor Selective Compound: Comparisons With Proposed Solution Conformations, J.Am. Chem. Soc., 116, 7523-7531 (1994).
  9. Nicolás, E. Russell, K.C. and Hruby, V.J., Asymmetric 1,4-Addition of Organocuprates to Chiral α,β-Unsaturated N-Acyl-4-Phenyl-2-Oxazolidinones:  A New Approach to the Synthesis of Chiral β-Branched Carboxylic Acids, J. Org. Chem., 58, 766-770 (1993).
  10. Qian, X., Russell, K.C., Boteju, L.W. and Hruby, V.J., Stereoselective Total Synthesis of Topographically Constrained Designer Amino Acids: 2', 6'-Dimethyl-β-Methyltyrosines, Tetrahedron, 51, 1033-1054 (1995).
  11. Soloshonok, V.A., Cai, C., Yamada, T., Ueki, H., Ohfune, Y. and Hruby, V.J., Michael Addition Reactions between Chiral Equivalents of a Nucleophilic Glycine and (S)- or (R)-3-[(E)-Enoyl]-4-phenyl-1,3-oxazolidin-2-ones as a General Method for Efficient Preparation of β-Substituted Pyroglutamic Acids. Case of Topographically Controlled Stereoselectivity, J. Am. Chem. Soc., 127, 15296-15303 (2005). PMC1851941
  12. Liu, Z., Mehta, S.J. and Hruby, V.J., Strategies for Asymmetric Synthesis of Amino Acids with δ/γ- Unsaturation’, Organic Preparations and Procedures International, 44, 222-255 (2012).
  13. Lam, K.S., Salmon, S.E., Hersh, E.M., Hruby, V.J., Kazmierski, W.M. and Knapp, R.J., A New Type of Synthetic Peptide Library for Identifying Ligand-Binding Activity, Nature, 354, 82-84 (1991).
  14. Lam, K.S., Hruby, V.J., Lebl, M., Knapp, R.J., Kazmierski, W.M., Hersh, E.M. and Salmon, S.E., The Chemical Synthesis of Large Random Peptide Libraries and Their Use For the Discovery of Ligands for Macromolecular Acceptors, Bioorganic & Medicinal Chemistry Letters, 3, 419-424 (1993).
  15. Hruby, V.J., Synthesis of Peptide Libraries for Lead Structure Screening, The Practice of Medicinal Chemistry, C.G. Wermuth, Ed., Academic Press, London, Chapter 9, 135-151 (1996).
  16. Horan, P.J., Mattia, A., Bilsky, E.J., Weber, S.J., Davis, T.P., Yamamura, H.I., Malatynska, E., Applyard, S.M., Slaninová, J., Misicka, A., Lipkowski, A.W., Hruby, V.J. and Porreca, F., Antinociceptive Profile of Biphalin, A Dimeric Enkephalin Analog, J. Pharmacol. Exp. Ther., 265, 1446-1454 (1993).
  17. Hruby, V.J., Porreca, F., Yamamura, H.I., Tollin, G., Agnes, R.S., Lee, Y.S., Cai, M., Alves, I., Cowell, S., Varga, E., Davis, P., Salamon, Z., Roeske, W., Vanderah, T. and Lai, J., New Paradigms and Tools in Drug Design for Pain and Addiction, Am. Assoc. Pharm. Sci. J., 8(3), E450-E460 (2006). PMCID: PMC1764851
  18. Yamamoto, T., Nair, P., Jacobsen, N.E., Davis, P., Ma, S-W, Navratilova, E., Moye, S., Lai, J., Yamamura, H.I., Vanderah, T.W., Porreca, F. and Hruby, V.J., The Importance of Micelle-Bound States for the Bioactivities of Bifunctional Peptide Derivatives for δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists, J. Med. Chem., 51, 6334-6347 (2008). PMC18821747
Collaborative Research: 
Ongoing:
5R01 GM10840-02                                (Hruby/Cai, MPI)                                            01/15/14-11/30/17
NIH/NIGMS
Designing Novel Melanotropins for Novel Applications for the Melanocortin System
The major goal of this grant is the design, synthesis, conformational analysis, pharmacological and physiological evaluation or novel receptor selective orthosteric and allosteric ligands for the melanocortin receptors for applications to feeding behavior, sexual behavior, pain, cancer and other biological effects. 
 
3R01 GM10840-02S1                            (Hruby/Cai, MPI)                                            01/14/14-11/30/17
NIH/NIGMS (Supplement)
Designing Novel Melanotropins for Novel Applications for the Melanocortin System
The major goal of this grant is the design, synthesis, conformational analysis, pharmacological and physiological evaluation or novel receptor selective orthosteric and allosteric ligands for the melanocortin receptors for applications to feeding behavior, sexual behavior, pain, cancer and other biological effects. 
 
3P01 DA06284-22S1                             (Hruby/Porreca, MPI)                                     03/31/89-03/31/16
NIH/NIDA
Design of Novel Ligands with Unique Biological Profiles for Neuropathic Pain
New Modalities for Treatment of Pain and Drug Abuse
The major goals of this Program Project are to design, develop, and examine new peptide ligands that are designed to have mu-delta opioid agonist activity and antagonist activities at anti-opioid receptors in pain pathways; to discover new modalities for treatment of pain and drug abuse; to discover new mechanisms of pain modulation; and to evaluate the chemical/physical properties of peptides that will maximize their biodistribution in vivo.
 
5R01 DA13449-06                                (Hruby, PI)                                                     09/01/09-01/31/16
NIH/NIDA
Novel Non-Peptide Opioid Ligands for Pain
This research is for the design and development of synthetic methodology and biological evaluation of novel peptide non-peptide mimetic ligands for opioid receptors and other receptors. 
 
Completed:
4200781                                               (Renquist, PI)                                                 01/31/12-01/02/15
Found Animals Fund
Increasing the Circulating Half-Life of GuRH-RIP
The goal of this research is to develop hormone-protein conjugates with enhanced half-life in vivo for birth control in animals.
 
5R01 CA97360                                     (Gillies, PI)                                                      07/01/08-05/31/13
NIH/NCI
Multimeric Ligands for Targeting Melanoma
The major goal of this research is to develop platform technologies that will enable us to distinguish normal cells from melanoma cancer cells in vitro and in vivo for imaging and treatment by addressing the cell surface.
Role: Co-Investigator.

Professional Information

Positions and Honors: 
Positions:
2005-Present  Professor of Medical Pharmacology, University of Arizona
2005-Present  Professor of BIO5, University of Arizona
1989-Present  Regents Professor, University of Arizona
1982-Present  Professor of Arizona Research Laboratory (Joint Appointment), University of Arizona
1978-Present  Professor of Biochemistry and Molecular Biophysics (Joint Appointment), University of Arizona
1977-Present  Professor of Chemistry, University of Arizona
1975-1976     Guest Worker (NIH Research Fellowship), NIH (with Martin Rodbell)
1972-1977     Associate Professor, University of Arizona
1968-1972     Assistant Professor, University of Arizona
1967-1968     Research Associate, Cornell University (with Vincent du Vigneaud)
1965-1967     Instructor of Biochemistry, Cornell University Medical College
 
Honors:
2012           Roche-Meienhofer Award
2012           ACS Medicinal Chemistry Hall of Fame
2011           Murray Goodman Award (APS)
2009           Arthur C. Cope Scholar Award (ACS)
2009           Arizona Technology Innovator of the Year
2007           Goodman Lecturer, UCSD
2006           Distinguished Career Teaching Award, University of Arizona
2003           Nolan and Gloria Sommer Award
2002           Ralph T. Hirschmann Award (ACS)
2002           Cathay Award (China)
1999-2000 Humboldt Senior Scientist Award
1996           Blomquist Lecturer, Cornell
1993           Pierce (ne Merrifield) Award (APS)
1989           Doctor Honorus Causa, Free University of Brussels
1988           MERIT Award
1987           Javits Neuroscience Award
1984-1985 Guggenheim Fellowship
1981           Fellow - N.Y. Acad. Sci.
1979           Fulbright-Hays Fellow
1978-1979 Rector's Lectureship, Free Univ. of Brussels
1975-1976 Fellow - Am. Ins. of Chemists; PHS Fellow; Fellow - AAAS
1963-1965 Cornell University - NSF Cooperative Fellow
1960           University of North Dakota - Abbott Award; Coon Award; Magna cum laude 
Other Experience and Professional Memberships/Affiliations: 
2012-2013      Drug Discovery for Neuroscience, Study Section, NIH
2007-2012      Member, Drug Discovery Panel ZRG1 MNPS-C (09) F Study Section, NIH
2002                Co-Chair, Gordon Research Conference
2000-2005      Member, Special Emphasis Panel MDCN-5 Study Section, NIH
1999-2000      Visiting Professor, Technical Univ. Munich (with Horst Kessler), Senior Humboldt Fellow
1997-2006      Editor-in-Chief, J. Peptide Research
1993                Visiting Professor, California Institute of Technology (with Peter Dervan),
1993                Organized Keystone Symposium
1990-1991      President, American Peptide Society
1988-1996      Editor-in-Chief, Int. J. Peptide Protein Research
1987-1992      Editorial Board, J. Med. Chem. and currently 8 others
1985-1989      Member, Bio-organic and Natural Product Chemistry Study Section, NIH
1984-1991      Editorial Board, Life Sciences
1984-1985       Visiting Professor, Harvard University, (with Martin Karplus)
1983                Chairman, American Peptide Symposium, 1981-1983; Organized 8th Am. Peptide Symp.
1981-2006      Editorial Board, Journal of Protein Chemistry
1980-1984      Member, Physiological Chemistry Study Section, NIH
1979-1990      American Peptide Symposium Board, Secretary/Treasurer
1979                Rector's Lecturer, Free University of Brussels

Academic Information

Doctorate: 
Cornell University - Ph.D., Chemistry
Master's Degree: 
University of North Dakota - M.S., Chemistry
Undergraduate School: 
University of North Dakota - B.S., Chemistry, Mathematics