Synthesis and evaluation of aziridine and symmetry-based epoxide affinity labels for HIV-1 protease

Abstract

Affinity labels have been prepared for HIV-1 protease. The synthesis of three symmetry-based epoxides and an aziridine analog of 1,2-epoxy-3-(p-nitrophenoxy)propane (EPNP) are reported. Assay procedures were developed to allow testing for both reversible and irreversible inhibition of HIV-1 protease, based on an internally-quenched fluorogenic substrate. Of eleven compounds assayed for reversible inhibition, five demonstrated modest to potent activities (K$\rm\sb{i}$'s ranging from 70 $\mu$M to 10 nM).

Five compounds were tested for irreversible inhibition of the protease; of these, EPNP and three others were observed to inhibit the enzyme in a time-dependent manner consistent with irreversible inhibition. The aziridine analog of EPNP was found to be approximately fifteen times less potent than EPNP; two C$\sb2$ symmetric epoxides exhibited modes time-dependent inhibition of HIV-1 protease.