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Antimicrobial Agents and Chemotherapy, March 2009, p. 1013-1018, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01211-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Takeshi Naito,1 Kazuki Izumi,1 Eiichi Kodama,1* Yasuko Sakagami,1 Keiko Kajiwara,1 Hiroki Nishikawa,2 Kentaro Watanabe,2 Stefan G. Sarafianos,3 Shinya Oishi,2 Nobutaka Fujii,2 and Masao Matsuoka1

Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan,1 Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan,2 Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Missouri3

Received 12 September 2008/ Returned for modification 24 October 2008/ Accepted 23 December 2008

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.

* Corresponding author. Mailing address: Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Phone and Fax: 81-75-751-3986. E-mail: ekodama{at}virus.kyoto-u.ac.jp

{triangledown} Published ahead of print on 29 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1013-1018, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01211-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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