title: Anti-HIV-1 peptide derivatives based on the HIV-1 Co-receptor CXCR4.
abstract: The human immunodeficiency virus type 1 (HIV-1) uses CD4 and the co-receptor CCR5 or CXCR4 in the process of cell entry. The negatively charged extracellular domains of CXCR4 (CXCR4-ED) interact with positive charges on the V3 loop of gp120, facilitating binding via electrostatic interactions. The presence of highly conserved positively charged residues in the V3 loop suggests that CXCR4-ED-derived inhibitors might be broadly effective inhibitors. Synthetic peptide derivatives were evaluated for anti-HIV-1 activity. The 39-mer extracellular N-terminal region (NT) was divided into three fragments with 10-mer overlapping sites (N1-N3), and these linear peptides were synthesized. Peptide N1 contains Met 1-Asp 20 and shows significant anti-HIV-1 activity. Extracellular loops 1 and 2 (ECL1 and 2) were mimicked by cyclic peptides C1 and C2, which were synthesized by chemoselective cyclization. Cyclic peptides C1 and C2 show higher anti-HIV-1 activity than their linear peptide counterparts, L1 and L2. The cytotoxicities of C1 and C2 are lower than those of L1 and L2. These results indicate that Met 1-Asp 20 segments of the NT and cyclic peptides of ECL1 and ECL2 are potent anti-HIV-1 drug candidates.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062 (Japan).
authors.forename: Chie
authors.initials: C
authors.lastname: Hashimoto
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Narumi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsutsumi
authors.forename: Masaki
authors.initials: M
authors.lastname: Haseyama
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Murakami
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D019718:Receptors, CXCR4 / Q000737:chemistry / Q000378:metabolism*; D055672:Static Electricity; D016662:Virus Integration / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D010455:Peptides; D019718:Receptors, CXCR4
keywords: CXCR4; HIV‐1 entry inhibitors; antiviral agents; extracellular domains; peptides