title: SC29EK, a peptide fusion inhibitor with enhanced alpha-helicity, inhibits replication of human immunodeficiency virus type 1 mutants resistant to enfuvirtide.
abstract: Peptides derived from the alpha-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 alpha-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 alpha-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 alpha-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.
authors.affiliation: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Shogoin, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Naito
authors.forename: Kazuki
authors.initials: K
authors.lastname: Izumi
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Sakagami
authors.forename: Keiko
authors.initials: K
authors.lastname: Kajiwara
authors.forename: Hiroki
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Kentaro
authors.initials: K
authors.lastname: Watanabe
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
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: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000187:drug effects; D002942:Circular Dichroism; D024882:Drug Resistance, Viral / Q000187:drug effects* / Q000235:genetics; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; C540660:SC29EK peptide; D000077560:Enfuvirtide