title: 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.
abstract: 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.
authors.affiliation: Department of DNA Enzymology and Molecular Virology, Institute of Molecular Genetics, National Research Council, IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kataropoulou
authors.forename: Marco
authors.initials: M
authors.lastname: Viola
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: La Regina
authors.forename: Francesco
authors.initials: F
authors.lastname: Piscitelli
authors.forename: Romano
authors.initials: R
authors.lastname: Silvestri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
mesh_terms: 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
chemical_list: 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