Specific inhibition of the reverse transcriptase of human immunodeficiency virus type 1 and the chimeric enzymes of human immunodeficiency virus type 1 and type 2 by nonnucleoside inhibitors.
We have studied the effects of four nonnucleoside inhibitors, including the novel natural product inhibitor calanolide A, on molecular chimeras containing complementary segments of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) reverse transcriptases (RTs). All four compounds specifically inhibited the DNA polymerase activity of HIV-1 RT but had no apparent effect on the RNase H activity of this enzyme or on the DNA polymerase or RNase H activity of HIV-2 RT. Three of these compounds showed the generally expected patterns of resistance and susceptibility with the various chimeric RTs. However, the inhibition patterns of the chimeric RTs by calanolide A provided evidence that there is a segment between residues 94 and 157 in HIV-1 RT that is critical for inhibition. However, the data also suggest that there may be a second segment located between amino acids 225 and 427 in HIV-1 RT that is also important for specifying susceptibility to the drug.
Hizi
A
A
Department of Cell Biology and Histology, Sackler School of Medicine, Tel Aviv University, Israel.
Tal
R
R
Shaharabany
M
M
Currens
M J
MJ
Boyd
M R
MR
Hughes
S H
SH
McMahon
J B
JB
D000998:Antiviral Agents / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology*; D016254:Mutagenesis, Insertional; D039681:Pyranocoumarins; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors
D000998:Antiviral Agents; D003374:Coumarins; D039681:Pyranocoumarins; D011993:Recombinant Fusion Proteins; D018894:Reverse Transcriptase Inhibitors; C072416:reverse transcriptase, Human immunodeficiency virus 2; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; C075959:calanolide A