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AIDS. 2015 Jan 2;29(1):13-21. doi: 10.1097/QAD.0000000000000498.

Design of a highly potent HIV-1 fusion inhibitor targeting the gp41 pocket.

Author information

1
MOH Key Laboratory of Systems Biology of Pathogens and AIDS Research Center, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.

Abstract

OBJECTIVE:

T20 (Enfuvirtide), which is a 36-residue peptide derived from the C-terminal heptad repeat (CHR) of gp41, is the only clinically available HIV-1 fusion inhibitor, but it easily induces drug resistance, which calls for next-generation drugs.

DESIGN:

We recently demonstrated that the M-T hook structure can be used to design a short CHR peptide that specifically targets the conserved gp41 pocket rather than the T20-resistant sites. We attempted to develop more potent HIV-1 fusion inhibitors based on the structure-activity relationship of MT-SC22EK.

METHODS:

Multiple biophysical and functional approaches were performed to determine the structural features, binding affinities and anti-HIV activities of the inhibitors.

RESULTS:

The 23-residue peptide HP23, which mainly contains the M-T hook structure and pocket-binding sequence, showed a helical and trimeric state in solution. HP23 had dramatically improved binding stability and antiviral activity, and it was the most potent inhibitor of the M-T hook-modified and unmodified control peptides. More promisingly, HP23 was highly active in the inhibition of diverse HIV-1 subtypes, including T20 and MT-SC22EK resistant HIV-1 mutants, and it exhibited a high genetic barrier to the development of resistance.

CONCLUSION:

Our studies delivered an ideal HIV-1 fusion inhibitor that specifically targeted the highly conserved gp41 pocket and possessed potent binding and antiviral activity. Furthermore, HP23 can serve as a critical tool to explore the mechanisms of HIV-1 fusion and inhibition.

PMID:
25562490
DOI:
10.1097/QAD.0000000000000498
[Indexed for MEDLINE]

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