Jason ChrumaJason J. Chruma

Research Description

The overarching goal of my research is the development of selective molecular alternatives toward the treatment of viral infections, as well as medical crises currently addressed primarily by invasive surgical intervention (e.g., cancer, brain aneurysms and other vascular diseases, and endometriosis). Accomplishing this goal requires the discovery of unique chemical entities that will localize in and image exclusively the area of interest, and initiate an ameliorative biological response. Nature is continually providing new compounds, both peptides and small molecules, that exhibit specific and favorable biological activities. Therefore, a basic thrust of my research effort is directed at the synthesis and investigation of medicinally-intriguing natural products and analogs thereof.

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A majority of biological responses and activities are mediated via protein-protein interactions. Therefore, the abrogation and/or enhancement of specific protein-protein interactions is an attractive strategy to selectively activate or repress certain biological activities. β-Sheet interactions play a central role in many of these biologically relevant protein-protein interactions, but the rational design and synthesis of conformationally-constrained peptide backbones that mimic individual β-sheet partners is an underdeveloped discipline. Once more, I am following Nature's lead in addressing this issue, specifically the synthesis and investigation of conformationally-constrained peptide antibiotics and analogs thereof. These diarylether and/or biaryl-containing natural products are able to bind to specific peptide sequences primarily via β-sheet interactions, and thus elicit desirable biological responses. The efficient synthesis of these and related compounds requires the development of new techniques for the preparation of unnatural amino acids, as well as biaryl and diarylether linkages.

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Unique protein targets also provide attractive anchors for selectively binding to and imaging specific tissues, either diseased or healthy. Therefore, I am interested in combining advances in phage display selection and synthetic modifications of peptide leads in a combinatorial fashion to rapidly discover peptides containing non-coded amino acid sidechains that selectively and potently bind to important biological targets. These studies will help advance the central and driving role that chemists play in interdisciplinary biomedical research.

Representative Publications

Hydrophobic and electronic factors in the design of dialkylglycine decarboxylase mimics. J. J. Chruma; L. Liu; W. Zhou; R. Breslow Bioorg. Med. Chem. 2005. 13: 5873-5883.

Chiral Polyamines from Reduction of Polypeptides: Asymmetric Pyridoxamine-Mediated Transaminations. W. Zhou, N. Yerkes, J. J. Chruma, L. Liu, R. Breslow. Bioorg. Med. Chem. Lett. 2005. 15: 1351-1355.

Transamination Reactions with Multiple Turnovers Catalyzed by Hydrophobic Pyridoxamine Cofactors in the Presence of Polyethyleneimine Polymers. L. Liu, W. Zhou, J. Chruma, R. Breslow. J. Am. Chem. Soc. 2004. 126: 8136-8137.

Small-Molecule Inhibitors of HIV-1 Entry Block Receptor-Induced Conformational Changes in the Viral Envelope Glycoproteins. Z. Si, N. Madani, J. M. Cox, J. J. Chruma, J. C. Klein, A. Schön, N. Phan, L. Wang, A. C. Biorn, S. Cocklin, I. Chaiken, E. Freire, A. B. Smith, III, J. G. Sodroski. Proc. Nat. Acad. Sci. USA. 2004. 101: 5036-5041.

Localized Changes in the gp120 Envelope Glycoprotein Confer Resistance to Human Immunodeficiency Virus Entry Inhibitors BMS-806 and #155. N. Madani, A. L. Perdigoto, K. Srinivasan, J. M. Cox, J. J. Chruma, J. LaLonde, M. Head, A. B. Smith, III, J. G. Sodroski. J. Virol. 2004. 78: 3742-3752.

Complestatin Synthetic Studies: the Effect of the Amino Acid Configuration on Peptide Backbone Conformation in the Common Western BCD Macrocycle. A. B. Smith, III, J. J. Chruma, Q. Han, J. Barbosa. Bioorg. Med. Chem. Lett. 2004. 14: 1697-1702.

Glycoside Inhibitors: Synthesis of Enantiomerically Pure Aza-Sugars from Schiff Base Amino Esters via Tandem Reduction-Alkenylation and Osmylation. R. Polt, D. Sames, J. Chruma. J. Org. Chem. 1999. 60: 6147-6158.

General Method for the Synthesis of N–Methyl Amino Acids and N–Alkylated Amino Esters from O'Donnell's Schiff Base. J. J. Chruma, D. Sames, R. Polt. Tetrahedron Lett. 1997. 38: 5085-5086.