Structure-activity relationships of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]- 3'-spiro-5' '-(4' '-amino-1' ',2' '-oxathiole-2' ',2' '-dioxide)thymine derivatives as inhibitors of HIV-1 reverse transcriptase dimerization.
The polymerase activity of HIV-1 reverse transcriptase (RT) is entirely dependent on the heterodimeric structure of the enzyme. Accordingly, RT dimerization represents a target for the development of a new therapeutic class of HIV inhibitors. We previously demonstrated that the N-3-ethyl derivative of 2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5' '-(4' '-amino-1' ',2' '-oxathiole-2' ',2' '-dioxide)thymine (TSAO-T) destabilizes the inter-subunit interactions of HIV-1 RT [Sluis-Cremer, N.; Dmietrinko, G. I.; Balzarini, J.; Camarasa, M.-J.; Parniak, M. A. Biochemistry 2000, 39, 1427-1433]. In the current study, we evaluated the ability of 64 TSAO-T derivatives to inhibit RT dimerization using a novel screening assay. Five derivatives were identified with improved activity compared to TSAO-T. Four of these harbored hydrophilic or aromatic substituents at the N3 position. Furthermore, a good correlation between the ability of the TSAO-T derivatives to inhibit RT dimerization and the enzyme's polymerase activity was also observed. This study provides an important framework for the rational design of more potent inhibitors of RT dimerization.
Sluis-Cremer
Nicolas
N
Division of Infectious Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. cremern@dom.pitt.edu
Hamamouch
Noureddine
N
San Félix
Ana
A
Velazquez
Sonsoles
S
Balzarini
Jan
J
Camarasa
María-José
MJ
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D019281:Dimerization; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine