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 monocytederived 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.

Identification and Characterization of Enzymes Catalyzing Pyrazolopyrimidine Formation in the Biosynthesis of Formycin A

“…3 It also has antiviral activity against influenza virus A1 4 and human immunodeficiency virus type 1. 5 Being a C -nucleoside analog of adenosine ( 2 ), formycin A has been shown to be a potent inhibitor of various enzymes that accept adenosine as a substrate such as adenosine kinase from Mycobacterium tuberculosis , which is involved in the purine salvage pathway. 6 Likewise, formycin A and its analogs are also known to inhibit bacterial purine nucleoside phosphorylase, which has pharmaceutical significance.…”

Trends in antiviral strategies

“…When the pyrimidine analog N 4 -hydroxy CMP was present at the extracistronic position 15, it directed the incorporation of GMP slightly more efficiently than AMP, while at position 39 incorporation of AMP was three-fold higher than GMP (compare Flavell et al, 1974 andDomingo et al, 1976). New mutagenic nucleotides are currently being investigated as potential lethal mutagens for viruses (Harki et al, 2002(Harki et al, , 2006(Harki et al, , 2007Graci and Cameron, 2004;Dapp et al, 2014;Vivet-Boudou et al, 2015; among other studies). There is active research to apply drugs (or their derivatives) used in antibacterial or anticancer therapy to lethal mutagenesis of viruses (drug repositioning or drug repurposing; see Section 8.4 in Chapter 8).…”

Trends in Antiviral Strategies

“…New nucleotide analogs are currently being investigated as potential lethal mutagens for viruses (Harki et al, 2002(Harki et al, , 2006(Harki et al, , 2007Graci and Cameron, 2004;Beach et al, 2014;Dapp et al, 2014;Vivet-Boudou et al, 2015; among other studies). There is active research to apply drugs (or its derivatives) used in antibacterial or anticancer therapy to lethal mutagenesis of viruses, in a strategy known as drug repositioning or drug repurposing, quite extended in current pharmacology.…”