title: Design of a modular tetrameric scaffold for the synthesis of membrane-localized D-peptide inhibitors of HIV-1 entry.
abstract: The highly conserved HIV-1 gp41 "pocket" region is a promising target for inhibiting viral entry. PIE12-trimer is a protease-resistant trimeric d-peptide inhibitor that binds to this pocket and potently blocks HIV entry. PIE12-trimer also possesses a reserve of binding energy that provides it with a strong genetic barrier to resistance ("resistance capacitor"). Here, we report the design of a modular scaffold employing PEGs of discrete lengths for the efficient optimization and synthesis of PIE12-trimer. This scaffold also allows us to conjugate PIE12-trimer to several membrane-localizing cargoes, resulting in dramatically improved potency and retention of PIE12-trimer's ability to absorb the impact of resistance mutations. This scaffold design strategy should be of broad utility for the rapid prototyping of multimeric peptide inhibitors attached to potency- or pharmacokinetics-enhancing groups.
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine , 15 N Medical Drive East Room 4100, Salt Lake City, Utah 84112-5650, United States.
authors.forename: J Nicholas
authors.initials: JN
authors.lastname: Francis
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Redman
authors.forename: Debra M
authors.initials: DM
authors.lastname: Eckert
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kay
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010455:Peptides