RNase H active site inhibitors of human immunodeficiency virus type 1 reverse transcriptase: design, biochemical activity, and structural information.
Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antiviral effect was observed. Binding was demonstrated via a solid state structure of the isolated p15-Ec domain of HIV-1 RT showing inhibitor and two Mn(II) ions bound to the RNase H active site.
Department of Medicinal Chemistry, Gilead Sciences, Foster City, California 94404, USA. tkirschberg@gilead.com
Thorsten A
TA
Kirschberg
Mini
M
Balakrishnan
Neil H
NH
Squires
Tiffany
T
Barnes
Katherine M
KM
Brendza
Xiaowu
X
Chen
Eugene J
EJ
Eisenberg
Weili
W
Jin
Nilima
N
Kutty
Stephanie
S
Leavitt
Albert
A
Liclican
Qi
Q
Liu
Xiaohong
X
Liu
John
J
Mak
Jason K
JK
Perry
Michael
M
Wang
William J
WJ
Watkins
Eric B
EB
Lansdon
D002264:Carboxylic Acids; D020134:Catalytic Domain; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D016914:Ribonuclease H / Q000037:antagonists & inhibitors*
D002264:Carboxylic Acids; D011743:Pyrimidines; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D016914:Ribonuclease H