title: High potency of indolyl aryl sulfone nonnucleoside inhibitors towards drug-resistant human immunodeficiency virus type 1 reverse transcriptase mutants is due to selective targeting of different mechanistic forms of the enzyme.
abstract: Indolyl aryl sulfone (IAS) nonnucleoside inhibitors have been shown to potently inhibit the growth of wild-type and drug-resistant human immunodeficiency virus type 1 (HIV-1), but their exact mechanism of action has not been elucidated yet. Here, we describe the mechanism of inhibition of HIV-1 reverse transcriptase (RT) by selected IAS derivatives. Our results showed that, depending on the substitutions introduced in the IAS common pharmacophore, these compounds can be made selective for different enzyme-substrate complexes. Moreover, we showed that the molecular basis for this selectivity was a different association rate of the drug to a particular enzymatic form along the reaction pathway. By comparing the activities of the different compounds against wild-type RT and the nonnucleoside reverse transcriptase inhibitor-resistant mutant Lys103Asn, it was possible to hypothesize, on the basis of their mechanism of action, a rationale for the design of drugs which could overcome the steric barrier imposed by the Lys103Asn mutation.
authors.affiliation: Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy.
authors.forename: Reynel
authors.initials: R
authors.lastname: Cancio
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.forename: Rino
authors.initials: R
authors.lastname: Ragno
authors.forename: Marino
authors.initials: M
authors.lastname: Artico
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Martino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hübscher
authors.forename: Silvio
authors.initials: S
authors.lastname: Spadari
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects*; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; D054303:HIV Reverse Transcriptase