Abstract
The deep hydrophobic pocket of HIV-1 gp41 has been considered a drug target, but short-peptides targeting this site usually lack potent antiviral activity. By applying the M-T hook structure, we previously generated highly potent short-peptide fusion inhibitors that specifically targeted the pocket site, such as MT-SC22EK, HP23L, and LP-11. Here, the crystal structures of HP23L and LP-11 bound to the target mimic peptide N36 demonstrated the critical intrahelical and interhelical interactions, especially verifying that the hook-like conformation was finely adopted while the methionine residue was replaced by the oxidation-less prone residue leucine, and that addition of an extra glutamic acid significantly enhanced the binding and inhibitory activities. The structure of HP23L bound to N36 with two mutations (E49K and L57R) revealed the critical residues and motifs mediating drug resistance and provided new insights into the mechanism of action of inhibitors. Therefore, the present data help our understanding for the structure-activity relationship (SAR) of HIV-1 fusion inhibitors and facilitate the development of novel antiviral drugs.
Highlights
Entry of HIV-1 into target cells involves the binding of the trimeric viral envelope glycoprotein (Env), which comprises the surface subunit gp120 and the transmembrane subunit gp41, to the cell receptor CD4 and chemokine coreceptor CCR5 or CXCR4, which triggers a barrage of conformational changes in Env complexes that activate the activity of gp41 (Chan et al, 1997; Eckert and Kim, 2001; Colman and Lawrence, 2003)
We determined the crystal structures of HP23L and its lipid derivative LP-11 in complexes with the N-terminal heptad repeats (NHR)-derived target peptides N36 or N44, which revealed their critical binding residues and motifs relative to the potent anti-HIV activity
The crystal structures of HP23L and LP-11 bound to the target sequence have finely demonstrated the intra-helical and inter-helical interactions underlying the molecular basis of such inhibitors
Summary
Entry of HIV-1 into target cells involves the binding of the trimeric viral envelope glycoprotein (Env), which comprises the surface subunit gp120 and the transmembrane subunit gp41, to the cell receptor CD4 and chemokine coreceptor CCR5 or CXCR4, which triggers a barrage of conformational changes in Env complexes that activate the activity of gp41 (Chan et al, 1997; Eckert and Kim, 2001; Colman and Lawrence, 2003). The Oε1 atom of the side chain of Glu-119 accepted a strong hydrogen bond from the backbone NH group of Thr-116 (distance = 2.9 Å, angle = 167.99◦), which further stabilized the conformation of L-T hook structure and strengthened hydrophobic binding of the upstream Leu-115 with the hydrophobic pocket on the NHR trimer.
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