Cyclic peptide inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase interaction.

Varun Dewan, Tao Liu, Kuan-Ming Chen, Ziqing Qian, Yong Xiao, Lawrence Kleiman, Kiran V Mahasenan, Chenglong Li, Hiroshi Matsuo, Dehua Pei, Karin Musier-Forsyth

Ohio State Biochemistry Program, The Ohio State University, Columbus, 43210, United States.

ACS chemical biology 2012 Apr 20

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The human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) plays a critical role in the viral life cycle. The C-terminal domain (CTD) of CA binds to human lysyl-tRNA synthetase (hLysRS), and this interaction facilitates packaging of host cell tRNA(Lys,3), which serves as the primer for reverse transcription. Here, we report the library synthesis, high-throughput screening, and identification of cyclic peptides (CPs) that bind HIV-1 CA. Scrambling or single-residue changes of the selected peptide sequences eliminated binding, suggesting a sequence-specific mode of interaction. Two peptides (CP2 and CP4) subjected to detailed analysis also inhibited hLysRS/CA interaction in vitro. Nuclear magnetic resonance spectroscopy and mutagenesis studies revealed that both CPs bind to a site proximal to helix 4 of the CA-CTD, which is the known site of hLysRS interaction. These results extend the current repertoire of CA-binding molecules to a new class of peptides targeting a novel site with potential for development into novel antiviral agents.

Citation

Varun Dewan, Tao Liu, Kuan-Ming Chen, Ziqing Qian, Yong Xiao, Lawrence Kleiman, Kiran V Mahasenan, Chenglong Li, Hiroshi Matsuo, Dehua Pei, Karin Musier-Forsyth. Cyclic peptide inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase interaction. ACS chemical biology. 2012 Apr 20;7(4):761-9