Poster abstracts

Poster number 79 submitted by Varun Dewan

Discovery of Cyclic Peptide Inhibitors Against HIV-1 Capsid

Varun Dewan (Ohio State Biochemistry Program, The Ohio State University, Columbus, OH), Tao Liu (Ohio State Biochemistry Program, Department of Chemistry, The Ohio State University, Columbus, OH), Hiroshi Matsuo (Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455), Lawrence Kleiman (Lady Davis Institute for Medical Research and Mc Gill AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada), Dehua Pei (Ohio State Biochemistry Program, Department of Chemistry, The Ohio State University, Columbus, OH), Karin Musier-Forsyth (Ohio State Biochemistry Program, Department of Chemistry, The Ohio State University, Columbus, OH)

Abstract:
Human immunodeficiency virus type 1 (HIV-1) Capsid (CA) protein plays an important role in viral life cycle including the formation of a tRNALys,3 packaging complex with Lysyl tRNA synthetase (LysRS) and the formation of the conical infectious coat surrounding the genome. In this work, cyclic peptide libraries containing randomized amino acid sequences and different ring sizes were synthesized and screened against CA and the monomeric form of the CA-C terminal domain (WM-CA CTD). Cyclic Peptide 2 (CP2) and 4 (CP4) selected from the library showed strong binding (KD ~ 500 nM) to both CA and WM-CA CTD in vitro. CP2 and CP4 also inhibited LysRS-CA interaction with an IC50 value of 1 µM. Furthermore, Nuclear Magnetic Resonance (NMR) analysis of CP4 confirms the binding to a novel site on the protein surface. Ongoing work is aimed at solving the NMR structure of the inhibitors with the targeted HIV-1 protein.

Keywords: Cyclic Peptides, Capsid, Lysyl tRNA Synthetase