title: The amphiphilic properties of novenamines determine their activity as inhibitors of HIV-1 RNase H.
abstract: Few inhibitors of the RNase H function associated with the HIV-1 reverse 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 amphiphiles and contain one ionizable group. Hence, a priori, in aqueous solutions the inhibitors might exist in at least four different physical states, namely protonated monomers, ionized monomers, protonated micelles, and ionized micelles. The three inhibitors all yielded anomalous dose-response curves, indicating that the four molecular species have different inhibitory potentials. In order to identify the inhibitory species, 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 insoluble monomolecular layers at the air/water interface. The anomalies of the dose-response curves can be resolved by taking into account the fact that, in solution, the relative proportion of these molecules in each physical state depends on the pH and on their analytical concentration. Thus interpreted, the results indicate that RNase H is inhibited only by the ionized micellar form of these compounds and not by their monomeric form. Around their pKa (approximately pH 5), the three compounds reproducibly form uniformly sized, self-emulsified colloidal particles that may be used as an efficient drug delivery system.
authors.affiliation: Upjohn Company, Kalamazoo, Michigan 49001, USA.
authors.forename: I W
authors.initials: IW
authors.lastname: Althaus
authors.forename: K M
authors.initials: KM
authors.lastname: Franks
authors.forename: K B
authors.initials: KB
authors.lastname: Langley
authors.forename: F J
authors.initials: FJ
authors.lastname: Kézdy
authors.forename: T
authors.initials: T
authors.lastname: Peterson
authors.forename: S E
authors.initials: SE
authors.lastname: Buxser
authors.forename: D E
authors.initials: DE
authors.lastname: Decker
authors.forename: L A
authors.initials: LA
authors.lastname: Dolak
authors.forename: R G
authors.initials: RG
authors.lastname: Ulrich
authors.forename: F
authors.initials: F
authors.lastname: Reusser
mesh_terms: D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004655:Emulsions; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D008968:Molecular Conformation; D015394:Molecular Structure; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D004655:Emulsions; D004791:Enzyme Inhibitors; D009675:Novobiocin; C048272:novenamine; D016914:Ribonuclease H