University of Arizona
Department of Chemistry and Biochemistry
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.
