Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses

Abstract

The sensitivities of reverse transcriptases (RTs) from feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV) were directly compared. The two enzymes had similar sensitivities to three analogs of dTTP, namely, 3'-azido-3'-deoxythymidine 5'-triphosphate, 2',3'-dideoxythymidine 5'-triphosphate, and 2',3'-dideoxy-2',3'-didehydrothymidine 5'-triphosphate. Each of these analogs demonstrated competitive inhibition of both enzymes. Ki values for inhibition of FIV RT by these three inhibitors were 3.3, 6.7, and 1.8 nM, respectively; Ki values for inhibition of the HIV enzyme were 6.5, 5.9, and 8.3 nM, respectively. Ratios of the Ki for the inhibitor to the Km for the substrate were also determined for each inhibitor, and no differences between the two enzymes greater than threefold were observed. Inhibition constants for 3'-amino-3'-deoxythymidine 5'-triphosphate and 3'-fluoro-3'-deoxythymidine 5'-triphosphate were determined for FIV RT, and these were similar to published values for HIV RT. The activities of three dideoxynucleoside 5'-triphosphates against FIV RT were determined; ddGTP was slightly more potent than ddTTP, whereas both were much more effective than ddCTP. The activity of a noncompetitive inhibitor, phosphonoformate, was also examined with the FIV enzyme; it was much more active with poly(rA)-oligo(dT) as the template-primer than with poly(rC)-oligo(dG) or poly(rI)-oligo(dC).

Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine

“…These compounds appear to be selective for human retroviruses and were not active against herpes simplex virus type 1 or type 2 by a plaque assay in Vero cells, Friend murine retrovirus by a UV-XC assay in SC-1 cells, or feline leukemia virus-FAIDS in culture (data not shown). Moreover, FTC was found to be effective in culture against feline and simian immunodeficiency viruses; viruses with properties similar to those of HIV-1 and HIV-2 (24,25,47).…”

(R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine is a potent inhibitor of feline immunodeficiency virus infection

“…FIV infection of cats, like HIV type 1 (HIV-1) infection of humans, leads after an asymptomatic period to AIDS and is used as an animal model (25,30). Similarities between the reverse transcriptases (RTs) of FIV and HIV-1 have been demonstrated with respect to template specificity and magnesium requirement (9,23). Zidovudine (AZT [3Ј-azido-3Ј-deoxythymidine]) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) have shown to be effective inhibitors of FIV replication in vitro (13) and have been used successfully as prophylactic (13,20,26) and therapeutic (13,14,17) agents in experimentally and naturally FIV-infected cats.…”

Multiple-drug-resistant mutants of feline immunodeficiency virus selected with 2',3'-dideoxyinosine alone and in combination with 3'-azido-3'-deoxythymidine

“…FIV and human immunodeficiency virus type 1 (HIV-1) are similar in morphology, protein composition, and genome arrangement. Of particular importance to chemotherapeutic studies is the fact that the reverse transcriptase (RT) of FIV is similar to that of HIV-1 in its physical properties, catalytic activities, and susceptibilities to several RT inhibitors (4,(9)(10)(11). Moreover, FIV is susceptible to all of the RTtargeted antiviral agents approved for use in the treatment of AIDS (15).…”