title: Cyclic peptide inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase interaction.
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.
authors.affiliation: Ohio State Biochemistry Program, The Ohio State University, Columbus, 43210, United States.
authors.forename: Varun
authors.initials: V
authors.lastname: Dewan
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Kuan-Ming
authors.initials: KM
authors.lastname: Chen
authors.forename: Ziqing
authors.initials: Z
authors.lastname: Qian
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiao
authors.forename: Lawrence
authors.initials: L
authors.lastname: Kleiman
authors.forename: Kiran V
authors.initials: KV
authors.lastname: Mahasenan
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuo
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
authors.forename: Karin
authors.initials: K
authors.lastname: Musier-Forsyth
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D001665:Binding Sites; D036022:Capsid Proteins / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D057166:High-Throughput Screening Assays; D006801:Humans; D008250:Lysine-tRNA Ligase / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; D010456:Peptides, Cyclic; D054852:Small Molecule Libraries; D008250:Lysine-tRNA Ligase