SC29EK, a peptide fusion inhibitor with enhanced alpha-helicity, inhibits replication of human immunodeficiency virus type 1 mutants resistant to enfuvirtide.
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.
Naito
Takeshi
T
Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Shogoin, Kyoto, Japan.
Izumi
Kazuki
K
Kodama
Eiichi
E
Sakagami
Yasuko
Y
Kajiwara
Keiko
K
Nishikawa
Hiroki
H
Watanabe
Kentaro
K
Sarafianos
Stefan G
SG
Oishi
Shinya
S
Fujii
Nobutaka
N
Matsuoka
Masao
M
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*
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; C540660:SC29EK peptide; D000077560:Enfuvirtide