Design of HIV Protease Inhibitors Based on Inorganic Polyhedral Metallacarboranes

Abstract

HIV protease (HIV PR) is a primary target for anti-HIV drug design. We have previously identified and characterized substituted metallacarboranes as a new class of HIV protease inhibitors. In a structure-guided drug design effort, we connected the two cobalt bis(dicarbollide) clusters with a linker to substituted ammonium group and obtained a set of compounds based on a lead formula [H₂N-(8-(C₂H₄O)₂-1,2-C₂B₉H₁₀)(1′,2′-C₂B₉H₁₁)-3,3′-Co)₂]Na. We explored inhibition properties of these compounds with various substitutions, determined the HIV PR:inhibitor crystal structure, and computationally explored the conformational space of the linker. Our results prove the capacity of linker-substituted dual-cage cobalt bis(dicarbollides) as lead compounds for design of more potent inhibitors of HIV PR.