THE AMPHIPHILIC PROPERTIES OF NOVENAMINES DETERMINE THEIR ACTIVITY ASINHIBITORS OF HIV-1 RNASE-H

Few inhibitors of the RNase H function associated with the HIV-1 rever se transcriptase have been discovered to date. We observed that three novenamines, U-34445, U-35122, and U-35401, are specific inhibitors of the HIV-1 RT RNase H function. All three compounds are strong amphiph iles and contain one ionizable group. Hence, a priori, in aqueous solu tions the inhibitors might exist in at least four different physical s tates, namely protonated monomers, ionized monomers, protonated micell es, and ionized micelles. The three inhibitors all yielded anomalous d ose-response curves, indicating that the four molecular species have d ifferent inhibitory potentials. In order to identify the inhibitory sp ecies, the amphiphilic properties of these compounds were studied. It was established that in alkaline solutions, around pH 8, all compounds are ionized and form micelles at concentrations above their CMC. Both the protonated and the ionized forms of these molecules form stable i nsoluble monomolecular layers at the air/water interface. The anomalie s of the dose-response curves can be resolved by taking into account t he fact that, in solution, the relative proportion of these molecules in each physical state depends on the pH and on their analytical conce ntration. Thus interpreted, the results indicate that RNase H is inhib ited only by the ionized micellar form of these compounds and not by t heir monomeric form. Around their pK(a) (similar to pH 5), the three c ompounds reproducibly form uniformly sized, self-emulsified colloidal particles that may be used as an efficient drug delivery system.