JVI Accepts, published online ahead of print on 16 April 2008

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J. Virol. doi:10.1128/JVI.00319-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Identification of a Critical Motif for the HIV-1 gp41 Core Structure: Implication for Designing Novel Anti-HIV Fusion Inhibitors

Yuxian He^*, Jianwei Chen, Jingjing Li, Zhi Qi, Hong Lu, Mingxin Dong, Shibo Jiang, and Qiuyun Dai^*

AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; Institute of Biotechnology, Chinese Academy of Military Medical Sciences, Beijing 100071, China; Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10021, USA

^* To whom correspondence should be addressed. Email: heyuxian{at}yahoo.com. qy_dai{at}yahoo.com.

HIV-1 entry into the host cell involves a cascade of events and currently represents one of most attractive targets in the search for new antiviral drugs. The fusion-active gp41 core structure is a stable six-helix bundle (6-HB) folded by its trimeric N- and C-terminal heptad-repeats (NHR and CHR). Peptides derived from the CHR region of HIV-1 gp41 are potent fusion inhibitors, which target the NHR to block viral and cellular membrane fusion in a dominant-negative fashion. However, all CHR peptides reported to date are primarily derived from the residues 628-673 of the gp41, little attention has been paid to the upstream sequence of the pocket binding domain (PBD) in the CHR. Here, we have identified a motif (⁶²¹QIWNNMT⁶²⁷) located at the upstream region of the gp41 CHR, immediately adjacent to the PBD (⁶²⁸WMEWEREI⁶³⁵). Biophysical characterization demonstrated that this motif is critical for the stabilization of the gp41 6-HB core. The peptide CP621-652 containing the ⁶²¹QIWNNMT⁶²⁷ motif was able to interact with T21, a counterpart peptide derived from the NHR, to form a typical 6-HB structure with a high thermostability (Tm = 82°C). In contrast, the 6-HB formed by the peptides N36 and C34, which has been considered as a core structure of the fusion-active gp41, had a Tm of 64°C. Different from T-20 (brand name Fuseon) which is the first and only HIV-1 fusion inhibitor approved for clinical use, CP621-652 could efficiently block 6-HB formation in a dose-dependent manner. Significantly, CP621-652 had potent inhibitory activity against HIV-1-mediated cell-cell fusion and infection, especially against T-20 and C34-resistant virus. Therefore, our works provide important information for understanding the core structure of the fusion-active gp41 and for designing novel anti-HIV peptides.

This article has been cited by other articles:

• He, Y., Liu, S., Li, J., Lu, H., Qi, Z., Liu, Z., Debnath, A. K., Jiang, S. (2008). Conserved Salt Bridge between the N- and C-Terminal Heptad Repeat Regions of the Human Immunodeficiency Virus Type 1 gp41 Core Structure Is Critical for Virus Entry and Inhibition. J. Virol. 82: 11129-11139 [Abstract] [Full Text]  
• He, Y., Cheng, J., Lu, H., Li, J., Hu, J., Qi, Z., Liu, Z., Jiang, S., Dai, Q. (2008). Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains. Proc. Natl. Acad. Sci. USA 105: 16332-16337 [Abstract] [Full Text]