Conjugation of phosphonoacetic acid to nucleobase promotes a mechanism-based inhibition |
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| Authors: | Algirdas Mikalkėnas Bazilė Ravoitytė Daiva Tauraitė Elena Servienė Rolandas Meškys |
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| Institution: | 1. Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania;2. Laboratory of Genetics, Nature Research Centre, Vilnius, Lithuania;3. Department of Molecular Microbiology and Biotechnology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania;4. Department of Chemistry and Bioengineering, Vilnius Gediminas Technical University, Vilnius, Lithuania;5. Laboratory of Genetics, Nature Research Centre, Vilnius, Lithuania |
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| Abstract: | Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors. |
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