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An effective conjugation strategy for designing short peptide-based HIV-1 fusion inhibitors.

An effective conjugation strategy for designing short peptide-based HIV-1 fusion inhibitors.
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Liang G, Wang H, Chong H, Cheng S, Jiang X, He Y, Wang C, Liu K,


Liang G, Wang H, Chong H, Cheng S, Jiang X, He Y, Wang C, Liu K, (click to view)

Liang G, Wang H, Chong H, Cheng S, Jiang X, He Y, Wang C, Liu K,

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Organic & biomolecular chemistry 14(33) 7875-82 doi 10.1039/c6ob01334a

Abstract

Lengthy peptides corresponding to the C-terminal heptad repeat (C-peptides) of human immunodeficiency virus type 1 (HIV-1) gp41 are potent inhibitors against virus-cell fusion. Designing short C-peptide-based HIV-1 fusion inhibitors could potentially redress the physicochemical and technical liabilities of a long-peptide therapeutic. However, designing such inhibitors with high potency has been challenging. We generated a conjugated architecture by incorporating small-molecule inhibitors of gp41 into the N-terminus of a panel of truncated C-peptides. Among these small molecule-capped short peptides, the 26-residue peptide Indole-T26 inhibited HIV-1 Env-mediated cell-cell fusion and viral replication at low nanomolar levels, reaching the potency of the only clinically used 36-residue peptide T20 (enfuvirtide). Collectively, our work opens up a new avenue for developing short peptide-based HIV-1 fusion inhibitors, and may have broad applicability to the development of modulators of other class I fusion proteins.

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