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

2006; BioMed Central; Volume: 3; Issue: S1 Linguagem: Inglês

10.1186/1742-4690-3-s1-s13

1742-4690

Kevin S. Harris, Dmitri S. Sergueev, John M. Reno,

DNA and Nucleic Acid Chemistry

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.