The capsid (CA) domain of human immunodeficiency virus (HIV) Gag polyprotein plays a critical role in viral assembly. The C-terminal domain (CTD) of CA also binds to human lysyl-tRNA synthetase (LysRS). This interaction is responsible for packaging host cell tRNALys,3, which serves as the primer in reverse transcription. In this work, we carried out high-throughput synthesis and screening of a bead-bound cyclic peptide library (3 x 105) against HIV-1 CA and identified a few peptides as potential HIV inhibitors. The identity of the �hits� was determined by sequencing the linear form of each peptide encoded on the inside of the bead. Two peptides showed strong binding (Kd ~ 500 nM) to both CA and CA-CTD and inhibited the LysRS-CA interaction in vitro. Chemical-shift perturbation NMR analyses suggested that CP4 binds to a site proximal to helix 4 of the CTD, which is the known site of LysRS interaction.

Discovery of cyclic peptides that bind HIV-1 capsid

240th National Meeting (2010)

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