Abstract
BackgroundPeptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp41 such as T20 (Enfuvirtide) and C34 are potent viral fusion inhibitors. We have recently found that two N-terminal residues (Met115 and Thr116) of CHR peptides form a unique M-T hook structure that can greatly enhance the binding and anti-HIV activity of inhibitors. Here, we applied two M-T hook residues to optimize SC29EK, an electrostatically constrained peptide inhibitor with a potent anti-HIV activity.ResultsThe resulting peptide MT-SC29EK showed a dramatically increased binding affinity and could block the six-helical bundle (6-HB) formation more efficiently. As expected, MT-SC29EK potently inhibited HIV-1 entry and infection, especially against those T20- and SC29EK-resistant HIV-1 variants. More importantly, MT-SC29EK and its short form (MT-SC22EK) suffered from the difficulty to induce HIV-1 resistance during the in vitro selection, suggesting their high genetic barriers to the development of resistance.ConclusionsOur studies have verified the M-T hook structure as a vital strategy to design novel HIV-1 fusion inhibitors and offered an ideal candidate for clinical development.
Highlights
Peptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp41 such as T20 (Enfuvirtide) and C34 are potent viral fusion inhibitors
The crystal structure of 6-HB core reveals a deep hydrophobic pocket on the C-terminal portion of N-terminal heptad repeat region (NHR) trimer, which is inserted by three hydrophobic residues from the pocket-binding domain (PBD) of CHR [12,13,14]
The M-T hook residues dramatically enhance the stability of 6-HB core To validate a general role of the M-T hook structure and develop a more active HIV-1 fusion inhibitor, we generated the peptide MT-SC29EK by adding the residues methionine (Met115) and thronine (Thr116) into the N-terminus of SC29EK
Summary
Peptides derived from the C-terminal heptad repeat (CHR) of HIV-1 gp such as T20 (Enfuvirtide) and C34 are potent viral fusion inhibitors. We have recently found that two N-terminal residues (Met115 and Thr116) of CHR peptides form a unique M-T hook structure that can greatly enhance the binding and anti-HIV activity of inhibitors. We applied two M-T hook residues to optimize SC29EK, an electrostatically constrained peptide inhibitor with a potent anti-HIV activity. The transmembrane subunit gp (Figure 1) inserts its fusion peptide (FP) into the cell membrane and packs its three C-terminal heptad repeat region (CHR) onto three N-terminal heptad repeat region (NHR) to form a six-helical bundle (6-HB) structure that bridges the viral and cellular membranes into a close proximity for fusion. The salt-bridge structures were introduced into C34 sequence creating
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