Open AccessSC29EK, a Peptide Fusion Inhibitor with Enhanced α-Helicity, Inhibits Replication of Human Immunodeficiency Virus Type 1 Mutants Resistant to Enfuvirtide
Author(s) -
Toshio Naito,
Keisuke Izumi,
Eiichi Kodama,
Yasuko Sakagami,
Keiko Kajiwara,
Hiroki Nishikawa,
Kentaro Watanabe,
Stefan G. Sarafianos,
Shinya Oishi,
Nobutaka Fujii,
Masao Matsuoka
Publication year - 2009
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01211-08
Subject(s) - enfuvirtide , gp41 , biology , peptide , virology , viral replication , lipid bilayer fusion , ritonavir , mutant , peptidomimetic , protease , wild type , reverse transcriptase , amino acid , microbiology and biotechnology , biochemistry , virus , rna , viral load , enzyme , genetics , epitope , antibody , antiretroviral therapy , gene
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 α-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.