title: Discovery of novel ribonucleoside analogs with activity against human immunodeficiency virus type 1.
abstract: Reverse transcription is an important early step in retrovirus replication and is a key point targeted by evolutionarily conserved host restriction factors (e.g., APOBEC3G, SamHD1). Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a major target of antiretroviral drugs, and concerns regarding drug resistance and off-target effects have led to continued efforts for identifying novel approaches to targeting HIV-1 RT. Several observations, including those obtained from monocyte-derived macrophages, have argued that ribonucleotides and their analogs can, intriguingly, impact reverse transcription. For example, we have previously demonstrated that 5-azacytidine has its greatest antiviral potency during reverse transcription by enhancement of G-to-C transversion mutations. In the study described here, we investigated a panel of ribonucleoside analogs for their ability to affect HIV-1 replication during the reverse transcription process. We discovered five ribonucleosides-8-azaadenosine, formycin A, 3-deazauridine, 5-fluorocytidine, and 2'-C-methylcytidine-that possess anti-HIV-1 activity, and one of these (i.e., 3-deazauridine) has a primary antiviral mechanism that involves increased HIV-1 mutational loads, while quantitative PCR analysis determined that the others resulted in premature chain termination. Taken together, our findings provide the first demonstration of a series of ribonucleoside analogs that can target HIV-1 reverse transcription with primary antiretroviral mechanisms that include premature termination of viral DNA synthesis or enhanced viral mutagenesis.
authors.affiliation: Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dapp
authors.forename: Laurent
authors.initials: L
authors.lastname: Bonnac
authors.forename: Steven E
authors.initials: SE
authors.lastname: Patterson
authors.forename: Louis M
authors.initials: LM
authors.lastname: Mansky
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D016133:Polymerase Chain Reaction; D012263:Ribonucleosides / Q000494:pharmacology*; D014158:Transcription, Genetic; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D017931:DNA Primers; D012263:Ribonucleosides