The chemistry and biology of KP-1461, a selective nucleoside mutagen for HIV therapy

  • Kevin Harris1,

    Affiliated with

    • Dmitri Sergueev1 and

      Affiliated with

      • John Reno1Email author

        Affiliated with

        Retrovirology20063(Suppl 1):S13

        DOI: 10.1186/1742-4690-3-S1-S13

        Published: 21 December 2006

         

        KP-1461 is a deoxycytidine analogue that is randomly inserted into HIV DNA by reverse transcriptase where it can cause base mispairing and introduce mutations that decrease viral fitness. The nucleoside consists of a natural deoxyribose for efficient use by the viral polymerase and a modified base that undergoes tautomerization between a cytosine form and a thymine form that exclusively causes transitional mutations. In vitro testing showed ablation of HIV when used in a serial passage format [1]. Host cell nuclear polymerases alpha and beta have a high Km for KP-1461 triphosphate that could preclude incorporation into nuclear DNA. KP-1461 has successfully completed preclinical testing including animal toxicology studies, a complete panel of genotoxicity assessments, and acute cardio, pulmonary and neurotoxicity tests. A single dose Phase 1a clinical trial in healthy volunteers showed safety and PK to continue clinical development. A Phase 1b study is currently underway in ARV-experienced HIV+ patients.

        Authors’ Affiliations

        (1)
        Koronis Pharmaceuticals, Inc

        References

        1. Harris KS, Brabant W, Styrchak S, Gall A: Daifuku R KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis. Antiviral Res 2005, 67: 1–9.View ArticlePubMed

        Copyright

        © Harris 2006

        This article is published under license to BioMed Central Ltd.

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