Dihydroxythiophenes are novel potent inhibitors of human immunodeficiency virus integrase with a diketo acid-like pharmacophore.
We have identified dihydroxythiophenes (DHT) as a novel series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors with broad antiviral activities against different HIV isolates in vitro. DHT were discovered in a biochemical integrase high-throughput screen searching for inhibitors of the strand transfer reaction of HIV-1 integrase. DHT are selective inhibitors of integrase that do not interfere with virus entry, as shown by the inhibition of a vesicular stomatitis virus G-pseudotyped retroviral system. Moreover, in quantitative real-time PCR experiments, no effect on the synthesis of viral cDNA could be detected but rather an increase in the accumulation of 2-long-terminal-repeat cycles was detected. This suggests that the integration of viral cDNA is blocked. Molecular modeling and the structure activity relationship of DHT demonstrate that our compound fits into a two-metal-binding motif that has been suggested as the essential pharmacophore for diketo acid (DKA)-like strand transfer inhibitors (Grobler et al., Proc. Natl. Acad. Sci. USA 99:6661-6666, 2002.). This notion is supported by the profiling of DHT on retroviral vectors carrying published resistance mutations for DKA-like inhibitors where DHT showed partial cross-resistance. This suggests that DHT bind to a common site in the catalytic center of integrase, albeit with an altered binding mode. Taken together, our findings indicate that DHT are novel selective strand transfer inhibitors of integrase with a pharmacophore homologous to DKA-like inhibitors.
Kehlenbeck
S
S
Antiinfective Research, Virology, Pharma Research Center, Bayer HealthCare AG, D-42096 Wuppertal, Germany.
Betz
U
U
Birkmann
A
A
Fast
B
B
Göller
A H
AH
Henninger
K
K
Lowinger
T
T
Marrero
D
D
Paessens
A
A
Paulsen
D
D
Pevzner
V
V
Schohe-Loop
R
R
Tsujishita
H
H
Welker
R
R
Kreuter
J
J
Rübsamen-Waigmann
H
H
Dittmer
F
F
D020816:Amino Acid Motifs; D001665:Binding Sites / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019427:HIV Integrase / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000378:metabolism; D016662:Virus Integration / Q000187:drug effects* / Q000235:genetics
D018076:DNA, Complementary; D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase