Non-nucleoside HIV-1 reverse transcriptase inhibitors di-halo-indolyl aryl sulfones achieve tight binding to drug-resistant mutants by targeting the enzyme-substrate complex.
Indolyl aryl sulfone (IAS) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have been previously shown to effectively inhibit wild-type (wt) and drug-resistant human immunodeficiency virus type 1 (HIV-1) replication. IASs proved to act through different mechanisms of action, depending on the nature and position of their chemical substituents. Here we describe selected novel IAS derivatives (di-halo-IASs). Our results show that these compounds are selective for the enzyme-substrate complex. The molecular basis for this selectivity was a different dissociation 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 resistant enzymes carrying the single mutations Lys103Asn, Leu100Ile, and Tyr181Ile (K103N, L100I, and Y181I), we found that one compound (RS1914) dissociated from the mutated enzymes almost 10-fold slower than from the wild type RT. These results demonstrate that IASs are very flexible molecules, interacting dynamically with the viral RT, and that this property can be successfully exploited to design inhibitors endowed with an enhanced binding to common NNRTI-resistant mutants.
Samuele
Alberta
A
Department of DNA Enzymology and Molecular Virology, Institute of Molecular Genetics, National Research Council, IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
Kataropoulou
Alexandra
A
Viola
Marco
M
Zanoli
Samantha
S
La Regina
Giuseppe
G
Piscitelli
Francesco
F
Silvestri
Romano
R
Maga
Giovanni
G
D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D006678:HIV / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D009154:Mutation; D011485:Protein Binding / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology
D019380:Anti-HIV Agents; D006827:Hydantoins; D018894:Reverse Transcriptase Inhibitors; D013450:Sulfones; C039283:di-halo; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase