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.
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.
Cancio
Reynel
R
Istituto di Genetica Molecolare IGM-CNR, via Abbiategrasso 207, I-27100 Pavia, Italy.
Silvestri
Romano
R
Ragno
Rino
R
Artico
Marino
M
De Martino
Gabriella
G
La Regina
Giuseppe
G
Crespan
Emmanuele
E
Zanoli
Samantha
S
Hübscher
Ulrich
U
Spadari
Silvio
S
Maga
Giovanni
G
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*
D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; D054303:HIV Reverse Transcriptase