The effect of certain N-tritylated phenylalanine conjugates of amino-adenosine-3',5'-cyclic monophosphate on moloney murine leukaemia virus reverse transcriptase activity

Van Zyl, Johann M. ; Ariatti, Mario ; Hawtrey, Arthur O. (2010-07)

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Moloney murine leukaemia virus M-MuLV) is a member of the retrovirus family. Its cloned reverse transcriptase RT), similarly to HIV type 1 reverse transcriptase HIV-1 RT), exhibits DNA-polymerase and ribonuclease H RNase H) activities capable of converting the single-stranded retroviral RNA genome into double-stranded DNA. The latter is then integrated into the host chromosome during viral infection. M-MuLV RT is, therefore, an attractive enzyme to help understand mutations in HIV-1 RT and its use in inhibition studies can help facilitate new drug designs. In this study, conjugates consisting of N-trityl derivatives of p-fluoro, p-nitro and p-iodo-DL-phenylalanine were coupled to 8-6-aminohexyl) amino-adenosine-3',5'-cyclic monophosphate and examined for their effect on DNA synthesis by M-MuLV RT. Synthesis was studied in a system containing poly rA).oligo dpT)15 as a template-primer with [ 3H] dTTP. The iodo-derivative, N-trityl-p-iodo-DL-phenylalanine-8-6- aminohexyl) amino-adenosine-3',5'-cyclic monophosphate was found to be a very active inhibitor of the RT enzyme IC50 = 1 μM), while the p-nitro IC50 = 45 μM) and p-fluoro IC50 = 65 μM) were weak inhibitors. Further work will be aimed at determining the mode of binding of the N-tritylated conjugates and also of various substituted amino acids and short peptides to M-MuLV RT to elucidate the mechanisms of inhibition. © 2010. The Authors.

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