9 research outputs found
Structure–Activity Relationship Studies of Indole-Based Compounds as Small Molecule HIV‑1 Fusion Inhibitors Targeting Glycoprotein 41
We
previously described indole-containing compounds with the potential
to inhibit HIV-1 fusion by targeting the hydrophobic pocket of transmembrane
glycoprotein gp41. Here we report optimization and structure–activity
relationship studies on the basic scaffold, defining the role of shape,
contact surface area, and molecular properties. Thirty new compounds
were evaluated in binding, cell–cell fusion, and viral replication
assays. Below a 1 μM threshold, correlation between binding
and biological activity was diminished, indicating an amphipathic
requirement for activity in cells. The most active inhibitor <b>6j</b> exhibited 0.6 μM binding affinity and 0.2 μM
EC<sub>50</sub> against cell–cell fusion and live virus replication
and was active against T20 resistant strains. Twenty-two compounds
with the same connectivity displayed a consensus pose in docking calculations,
with rank order matching the biological activity. The work provides
insight into requirements for small molecule inhibition of HIV-1 fusion
and demonstrates a potent low molecular weight fusion inhibitor