As an effort to develop novel antiviral compounds, we are developing KNI-272, a transition-state mimetic tripeptide HIV protease inhibitor containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenyl- butyric acid]. KNI-272 was first administered to patients with advanced HIV-1 infection at the Medicine Branch in March 1994. We have now found that certain mutations occurring in the protease-encoding region can confer on HIV-1 resistance to KNI 272 in vitro. We have more recently identified several Apns-containing protease inhibitors which are active against both wild-type HIV-1 and HIV-1 variants resistant to KNI-272. The accumulating data suggest that the development of HIV-1 variants with reduced susceptibility to reverse transcriptase (RT) inhibitors is related to clinical deterioration in patients receiving combination therapy with multiple RT inhibitors (e.g., AZT/ddC and AZT/ddI). In this regard, we have identified a set of novel mutations [Ala-62 Val(A62V), V75I, F77L, F116Y, and Q151M] in the polymerase domain of RT of HIV-1, which confers on the virus a reduced sensitivity to multiple antiretroviral dideoxynucleosides (ddNs). We have recently defined virological and enzymatic properties of such mutations. In another area of our research efforts to optimize the antiviral activity of nucleoside RT inhibitors, we have demonstrated differential anti-HIV-1 activity of ddNs in phytohemagglutinin-activated peripheral blood mononuclear cells (PHA-PBM) and resting PBM. We have also found that hydroxyurea (HU) can potentiate antiviral activity of ddNs, particularly that of ddI, through inhibition of deoxyribonucleotide reductase. These data suggest that modification of certain cellular enzymes may enhance the antiviral activity of anti-HIV-1 drugs, which may open a new avenue in designing combination chemotherapy of AIDS.
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