Significance The anti-HIV drug KP1212 was designed to intentionally increase the mutation rate of HIV, thereby causing viral population collapse. Its mutagenicity and thus antiviral activity was proposed to be the result of tautomerization. We used 2D IR spectroscopy to identify rapidly interconverting tautomers under physiological conditions. The traditionally rare enol–imino tautomer for nucleobases was found to be the major species for KP1212, providing a structural support for the tautomer hypothesis. We further found that KP1212 is significantly protonated at physiological pH with a pK a of 7. The protonated KP1212 was shown to be mutagenic, revealing a bimodal mutagenic property of KP1212. The results could prove instrumental in developing the next-generation antiviral treatments.

12 Aug 2014·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

Q1 · CROSS-FIELD

Article

Author: Simi, Allison K. ; Li, Deyu ; Tokmakoff, Andrei ; Essigmann, John M. ; Peng, Chunte Sam ; Simpson, Jeffrey H. ; Singh, Vipender ; Silvestre, Katherine J. ; Fedeles, Bogdan I.

SignificanceUnlike conventional antiviral therapy, lethal mutagenesis is a therapeutic strategy that exploits the high mutation rates of certain viruses. It works by intentionally increasing the viral mutation rate, causing excessive error accumulation and viral population collapse. The mutagenic nucleoside analog 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212) is specifically designed to use lethal mutagenesis against HIV. The mechanism of KP1212 mutagenesis was proposed to involve tautomerism—the repositioning of active protons on the nucleic acid base on a fast time scale. Using a multifaceted approach, we demonstrate that KP1212 exists in multiple tautomeric forms, and that the tautomeric distribution correlates with the mutagenic properties of KP1212. This work also provides a toolset for studying tautomerism in nucleic acids and developing the next-generation antiviral lethal mutagens.

01 Jun 2014·Antiviral ResearchQ2 · MEDICINE

Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) using pre-steady-state kinetics

Q2 · MEDICINE

Article

Author: Muftuoglu, Yagmur ; Anderson, Karen S ; Mislak, Andrea C ; Mitsuya, Hiroaki ; Sarafianos, Stefan G ; Sohl, Christal D

The novel antiretroviral 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a potent nucleoside HIV-1 reverse transcriptase (RT) inhibitor (NRTI). Unlike other FDA-approved NRTIs, EFdA contains a 3'-hydroxyl. Pre-steady-state kinetics showed RT preferred incorporating EFdA-TP over native dATP. Moreover, RT slowly inserted nucleotides past an EFdA-terminated primer, resulting in delayed chain termination with unaffected fidelity. This is distinct from KP1212, another 3'-hydroxyl-containing RT inhibitor considered to promote viral lethal mutagenesis. New mechanistic features of RT inhibition by EFdA are revealed.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 2	US	Koronis Pharmaceuticals, Inc.	01 Jul 2007
HIV Infections	Phase 2	PR	Koronis Pharmaceuticals, Inc.	01 Jul 2007

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