title: Multimerized HIV-gp41-derived peptides as fusion inhibitors and vaccines.
abstract: To date, several antigens based on the amino-terminal leucine/isoleucine heptad repeat (NHR) region of an HIV-1 envelope protein gp41 and fusion inhibitors based on the carboxy-terminal leucine/isoleucine heptad repeat (CHR) region of gp41 have been reported. We have developed a synthetic antigen targeting the membrane-fusion mechanism of HIV-1. This uses a template designed with C3-symmetric linkers and mimics the trimeric form of the NHR-derived peptide N36. The antiserum obtained by immunization of the N36 trimeric antigen binds preferentially to the N36 trimer and blocks HIV-1 infection effectively, compared with the antiserum obtained by immunization of the N36 monomer. Using another template designed with different C3-symmetric linkers, we have also developed a synthetic peptide mimicking the trimeric form of the CHR-derived peptide C34, with ∼100 times the inhibitory activity against the HIV-1 fusion mechanism than that of the monomer C34 peptide. A dimeric derivative of C34 has potent inhibitory activity at almost the same levels as this C34 trimer mimic, suggesting that presence of a dimeric form of C34 is structurally critical for fusion inhibitors. As examples of rising mid-size drugs, this review describes an effective strategy for the design of HIV vaccines and fusion inhibitors based on a relationship with the native structure of proteins involved in HIV fusion mechanisms. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 622-628, 2016.
authors.affiliation: Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-Ku, Tokyo 101-0062, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Nomura
authors.affiliation: Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-Ku, Tokyo 101-0062, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Department of Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-Ku, Tokyo 101-0062, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
mesh_terms: D016915:AIDS Vaccines / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry / Q000276:immunology; D006801:Humans; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000276:immunology; D055503:Protein Multimerization / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D015700:HIV Envelope Protein gp41; D010455:Peptides
keywords: C34 trimer; HIV fusion inhibitor; N36 trimer; vaccine