SC29EK, a Peptide Fusion Inhibitor with Enhanced α-Helicity, Inhibits Replication of Human Immunodeficiency Virus Type 1 Mutants Resistant to Enfuvirtide

• DOI: 10.1128/aac.01211-08
• Publication Date: 2008-12-30T04:54:53Z
• Authors: Takeshi Naito; Kazuki Izumi; Eiichi Kodama; Yasuko Sakagami; Keiko Kajiwara; Hiroki Nishikawa; Kentaro Watanabe; Stefan G. Sarafianos; Shinya Oishi; Nobutaka Fujii; Masao Matsuoka
• Keywords: Enfuvirtide; Ritonavir; Peptidomimetic; Wild type

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