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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)761-769
Number of pages9
JournalACS Chemical Biology
Volume7
Issue number4
DOIs
StatePublished - Apr 20 2012

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