Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent success of the fusion inhibitor T-20 (enfuvirtide) in clinical studies has ushered in a new chapter in the development of anti-HIV-1 therapeutics. T-20 is the first FDA-approved drug that targets the viral transmembrane protein gp41. This protein, along with gp120, promotes viral entry through a coordinated cascade of conformational transitions that lead to the fusion of the HIV-1 and target cell membranes. The interaction of gp120 with CD4 and a chemokine receptor stimulates gp41 to extend and bridge the space between the virus and cell. Subsequently, gp41 collapses into a trimer-of-hairpins structure that brings the viral and cellular membranes into close proximity necessary for fusion. Enfuvirtide targets the gp41 amino-terminal region exposed in the transient extended state, blocking the ultimate collapse into the trimer-of hairpins and inhibiting membrane fusion. The vulnerability of this transient extended state has stimulated the development of new agents, ranging from small molecules to large proteins, that bind to gp41 and inhibit its structural transformations. The discovery and characterization of these inhibitors have not only led to new antiviral strategies, but have also shed light on the accessibility of gp41 epitopes that might play a role in HIV-1 vaccine development.
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PMID:HIV-1 gp41 as a target for viral entry inhibition. 1518 May 42

Enfuvirtide (T20), the first FDA approved fusion inhibitor for HIV-1/AIDS, displayed outstanding effects of fusion inhibition by binding to the envelope glycoprotein gp41. But with the continuous emergence of T20-resistant mutations, the exploration of T20's binding mechanism onto gp41 wild type (WT) and the related resistance mechanism is needed. In this work, a complete structure model of gp41 including the fusion peptide (FP) and HR1 in complex with three molecules of T20 was obtained by structural modeling and molecular dynamics simulation (MDS). In this T20-gp41 model, the T20 hydrophobic C-terminal composed of the eight-residue sequence "WASLWNWF" formed unstructured coil instead of a helical structure, which enabled more residues of T20 to contact gp41 to exert its antiviral activity. Essential residues Trp155, Trp159, Trp161 and Phe162 of T20 formed strong vdW interactions with some hydrophobic cavities on the gp41, as never seen in other gp41 trimetric core structures. Based on the T20-gp41 model, seven corresponding structure models of T20-resistant mutants G36D, I37K, V38E, Q39H, Q41R, N43D and L45M were constructed and fully equilibrated by MDS. Most remarkably, the I37K and Q41R mutations led to collapse of the coiled coil structure, causing greatest change in binding energy. Also notably, the V38E and N43D mutations hindered the binding of T20 through electrostatic repulsion and thus also resulted in dramatic change in binding energy. Besides, mutations G36D, Q39H and L45M only caused minor conformational and energetic changes. In all, these results could provide new clues for the design of T20-like peptide inhibitors to target the T20-resistant virus.
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PMID:The binding mode of fusion inhibitor T20 onto HIV-1 gp41 and relevant T20-resistant mechanisms explored by computational study. 2233 24