title: Design of peptide-based inhibitors for human immunodeficiency virus type 1 strains resistant to T-20.
abstract: Enfuvirtide (T-20) is a fusion inhibitor that suppresses replication of human immunodeficiency virus (HIV) variants with multi-drug resistance to reverse transcriptase and protease inhibitors. It is a peptide derived from the C-terminal heptad repeat (C-HR) of HIV-1 gp41, and it prevents interactions between the C-HR and the N-terminal HR (N-HR) of gp41, thus interfering with conformational changes that are required for viral fusion. However, prolonged therapies with T-20 result in the emergence of T-20-resistant strains that contain primary mutations such as N43D in the N-HR of gp41 (where T-20 and C-HR bind) that help the virus escape at a fitness cost. Such variants often go on to acquire a secondary mutation, S138A, in the C-HR of gp41 region that corresponds to the sequence of T-20. We demonstrate here that the role of S138A is to compensate for the impaired fusion kinetics of HIV-1s carrying primary mutations that abrogate binding of T-20. To preempt this escape strategy, we designed a modified T-20 variant containing the S138A substitution and showed that it is a potent inhibitor of both T-20-sensitive and T-20-resistant viruses. Circular dichroism analysis revealed that the S138A provided increased stability of the 6-helix bundle. We validated our approach on another fusion inhibitor, C34. In this case, we designed a variant of C34 with the secondary escape mutation N126K and showed that it can effectively inhibit replication of C34-resistant HIV-1. These results prove that it is possible to design improved peptide-based fusion inhibitors that are efficient against a major mechanism of drug resistance.
authors.affiliation: Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Kyoto 606-8507, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Izumi
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Kazuya
authors.initials: K
authors.lastname: Shimura
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Sakagami
authors.forename: Kentaro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Saori
authors.initials: S
authors.lastname: Ito
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watabe
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Terakawa
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitaura
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D019943:Amino Acid Substitution; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects* / Q000235:genetics
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; C514787:gp41 protein, Human immunodeficiency virus 1; D000077560:Enfuvirtide