title: Identification and characterization of a novel HIV-1 nucleotide-competing reverse transcriptase inhibitor series.
abstract: Several groups have recently reported on the identification of nucleotide-competing reverse transcriptase inhibitors (NcRTIs), a new class of RT inhibitors. NcRTIs reversibly inhibit binding of the incoming nucleotide to the RT active site but do not act as chain terminators, unlike the nucleos(t)ide reverse transcriptase inhibitor (NRTI) class. We identified a novel benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI chemical series. Structure-activity relationship evaluation of this series with both RT and viral replication assays led to the identification of compound A, a new NcRTI. Compound A inhibited HIV-1 RT in a primer extension assay (50% inhibitory concentration, 2.6 nM) but had no measurable activity against human DNA polymerase γ at 10 μM. It potently inhibited HIV-1 replication in vitro (50% effective concentration, 1.5 nM). The antiviral potency of compound A was unaffected by the presence of nonnucleotide RT inhibitor (NNRTI) mutations tested (L100I, K103N/Y181C, V106A, or Y188L). Notably, viruses encoding K65R were hypersusceptible to inhibition by compound A. Compound A also retained full activity against viruses encoding M184V. In vitro selection for resistant virus to compound A led to the selection of a single substitution within RT: W153L. A recombinant virus encoding the RT W153L was highly resistant to compound A (fold change, 160). W153 is a highly conserved residue in HIV RT and has not been previously associated with drug resistance. In summary, a novel NcRTI series with optimized antiviral activity, minimal cross-resistance to existing RT inhibitor classes, and a distinct resistance profile has been discovered. These results further establish NcRTIs as an emerging class of antiretroviral agents.
authors.affiliation: Department of Biological Sciences, Boehringer Ingelheim Canada Ltd, Laval, Quebec, Canada. daniel.rajotte@boehringer-ingelheim.com
authors.forename: D
authors.initials: D
authors.lastname: Rajotte
authors.forename: S
authors.initials: S
authors.lastname: Tremblay
authors.forename: A
authors.initials: A
authors.lastname: Pelletier
authors.forename: P
authors.initials: P
authors.lastname: Salois
authors.forename: L
authors.initials: L
authors.lastname: Bourgon
authors.forename: R
authors.initials: R
authors.lastname: Coulombe
authors.forename: S
authors.initials: S
authors.lastname: Mason
authors.forename: L
authors.initials: L
authors.lastname: Lamorte
authors.forename: C F
authors.initials: CF
authors.lastname: Sturino
authors.forename: R
authors.initials: R
authors.lastname: Bethell
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D057166:High-Throughput Screening Assays; D006801:Humans; D008826:Microbial Sensitivity Tests; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication
chemical_list: D019380:Anti-HIV Agents; D001572:Benzofurans; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
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