HIV

Nucleosides are composed of a “base,” adenine, guanine, cytosine, uracil or thymine and a “sugar,” either ribose (incorporated into RNA) or deoxyribose (incorporated into DNA). Most all conventional nucleoside analogs used as antiviral medicines have modified sugars but with unmodified or natural bases. Examples of these drugs include acyclovir, lamivudine or zidovudine (AZT). In contradistinction, Koronis’ nucleosides contain the natural sugar but have modified bases.

Nucleoside analog reverse transcriptase inhibitors approved for HIV all have modified sugars that do not contain a 3’-OH and their mechanism of action can be described as “chain termination” meaning that viral reverse transcriptase cannot continue to extend the DNA genomic transcript because of the lack of a 3’-OH.

The use of a natural sugar in Koronis’ nucleoside drugs allows efficient recognition by the viral polymerase facilitating incorporation of the drug into the viral nucleic acid. It is fundamental to our technology that the modified base portion of the analog allow base-paring with more than one complementary base thus potentially causing a mutation to occur wherever it is incorporated. The following figure illustrates natural Watson-Crick base pairing in the left panel and in the right panel, the base pairing induced by incorporation of KP-1212 monophosphate into the viral genome. KP-1212 in the “C” or cytidine form makes base-pairs with guanosine. But, KP-1212 can tautomerize to a “T” or thymidine form and base pair with adenosine. Therefore, incorporation of KP-1212 can cause G to A and A to G mutations and, theoretically, C to T and T to C mutations. These purine to purine and pyrimidine to pyrimidine mutations are called transition mutations. Consistent with this mechanism, we have never observed transversion-type mutations, defined as purine to pyrimidine and vice versa mutations.

Ribavirin is a generic ribonucleoside analog currently used for treating respiratory syncytial virus (RSV) infections and hepatitis C virus (HCV) infections in combination with recombinant human interferon. It has been established that ribavirin is also a viral mutagen (Current Opinion in Infectious Diseases (2001) 14:757-764). In this case however, the ability of ribavirin to form rotational isomers and not tautomers is responsible for its ability to base pair with more than one complementary base.

Many nucleoside analogues have been studied as anti-cancer drugs and many have been shown to cause unacceptable side effects including cancer. It is a hallmark of Koronis' nucleoside drugs that they are not well recognized by host cell polymerases as substrates but are readily recognized by host cell DNA repair functions.

KP-1461 for the Treatment of HIV

KP-1461 is an oral prodrug of KP-1212, a nucleoside shown to be effective in cell culture against HIV-1 and HIV-2. It is also effective against virus with mutations conferring resistance to many of the drugs currently approved for treatment of HIV/AIDS. In preclinical cell culture studies, KP-1212 demonstrated an efficacy-dependent increase in random transitional mutations in the HIV genome without host cell toxicity.

The metabolism and activation of the prodrug to KP-1212-triphosphate, the active metabolite and substrate for viral reverse transcriptase (RT), is shown in the following figure.