Design of peptide-based inhibitors for human immunodeficiency virus type 1 strains resistant to T-20

Kazuki Izumi, Eiichi Kodama, Kazuya Shimura, Yasuko Sakagami, Kentaro Watanabe, Saori Ito, Tsuyoshi Watabe, Yukihiro Terakawa, Hiroki Nishikawa, Stefan G. Sarafianos, Kazuo Kitaura, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4914-4920
Number of pages7
JournalJournal of Biological Chemistry
Volume284
Issue number8
DOIs
Publication statusPublished - 2009 Feb 20
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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