SC29EK, a peptide fusion inhibitor with enhanced α-helicity, inhibits replication of human immunodeficiency virus type 1 mutants resistant to enfuvirtide

Takeshi Naito, Kazuki Izumi, Eiichi Kodama, Hiroki Nishikawa, Kentaro Watanabe, Yasuko Sakagami, Keiko Kajiwara, Stefan G. Sarafianos, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)

Abstract

Peptides derived from the α-helical domains of human immunodeficiency virus (HIV) type 1 (HIV-1) gp41 inhibit HIV-1 fusion to the cell membrane. Enfuvirtide (T-20) is a peptide-based drug that targets the step of HIV fusion, and as such, it effectively suppresses the replication of HIV-1 strains that are either wild type or resistant to multiple reverse transcriptase and/or protease inhibitors. However, HIV-1 variants with T-20 resistance have emerged; therefore, the development of new and potent inhibitors is urgently needed. We have developed a novel HIV fusion inhibitor, SC34EK, which is a gp41-derived 34-amino-acid peptide with glutamate (E) and lysine (K) substitutions on its solvent-accessible site that stabilize its a-helicity. Importantly, SC34EK effectively inhibits the replication of T-20-resistant HIV-1 strains as well as wild-type HIV-1. In this report, we introduce SC29EK, a 29-amino-acid peptide that is a shorter variant of SC34EK. SC29EK blocked the replication of T-20-resistant HIV-1 strains and maintained antiviral activity even in the presence of high serum concentrations (up to 50%). Circular dichroism analysis revealed that the α-helicity of SC29EK was well maintained, while that of the parental peptide, C29, which showed moderate and reduced inhibition of wild-type and T-20-resistant HIV-1 strains, was lower. Our results show that the α-helicity in a peptide-based fusion inhibitor is a key factor for activity and enables the design of short peptide inhibitors with improved pharmacological properties.

Original languageEnglish
Pages (from-to)1013-1018
Number of pages6
JournalAntimicrobial agents and chemotherapy
Volume53
Issue number3
DOIs
Publication statusPublished - 2009 Mar
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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