title: A multi-functional peptide as an HIV-1 entry inhibitor based on self-concentration, recognition, and covalent attachment.
abstract: HIV entry is mediated by the envelope glycoproteins gp120 and gp41. The gp41 subunit contains several functional domains: the N-terminal heptad repeat (NHR) domains fold a triple stranded coiled-coil forming a meta-stable prefusion intermediate. The C-terminal heptad repeat (CHR) subsequently folds onto the hydrophobic grooves of the NHR coiled-coil to form a stable 6-helix bundle, which juxtaposes the viral and cellular membranes for fusion. A conserved salt bridge between Lys(574) in NHR and Asp(632) in CHR plays an essential role in the formation of the six-helix bundle. A multi-functional peptide inhibitor for anti-HIV derived from the CHR of gp41 has been designed. It bears a cholesterol group (Chol) at the C-terminal through which the inhibitor can anchor in the cell membrane, and carries an isothiocyanate (NCS) group at the side chain of Asp(632) through which the inhibitor can bind to target covalently at Lys(574) in NHR. The dual functionalized peptide (NCS-C34-Chol) shows high antiviral activity in vitro and in vivo. The inhibitor reacts specifically and rapidly to NHR from gp41. In addition, it exhibits better stability under the digestion of the Proteinase K than C34 and T20.
authors: The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors: Lei
authors: L
authors: Zhao
authors: Pei
authors: P
authors: Tong
authors: Yong-Xiang
authors: YX
authors: Chen
authors: Zhi-Wen
authors: ZW
authors: Hu
authors: Kun
authors: K
authors: Wang
authors: Yu-Ning
authors: YN
authors: Zhang
authors: De-Sheng
authors: DS
authors: Zhao
authors: Li-Feng
authors: LF
authors: Cai
authors: Ke-Liang
authors: KL
authors: Liu
authors: Yu-Fen
authors: YF
authors: Zhao
authors: Yan-Mei
authors: YM
authors: Li
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D002784:Cholesterol / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D004591:Electrophoresis, Polyacrylamide Gel; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry*
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; D002784:Cholesterol