Borano-nucleotides: new analogues to circumvent HIV-1 RT-mediated nucleoside drug-resistance.
Alpha-boranophosphates suppress RT-mediated resistance when the catalytic rate of incorporation (kpol) of the analogue 5'-triphosphate is responsable for drug resistance, such as in the case of K65R mutant and ddNTPs, and Q151M toward AZTTP and ddNTPs. This suppression is also observed with BH3-d4T and BH3-3TC toward their clinically relevant mutants Q151M and M184V. Moreover, the presence of the borano (BH3-) group renders the incorporation of the analogue independent from amino-acid substitutions in RT. To our knowledge, this is the first example of rescue of polymerase activity by means of a nucleotide analogue.
Alvarez
Karine
K
CNRS, UMR 6098, Architecture et Fonction des Macromolecules Biologiques, Marseille Cedex 9, France.
Deval
Jérôme
J
Selmi
Boulbaba
B
Barral
Karine
K
Boretto
Joelle
J
Guerreiro
Catherine
C
Mulard
Laurence
L
Sarfati
Robert
R
Canard
Bruno
B
D000596:Amino Acids / Q000737:chemistry; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001895:Boron / Q000737:chemistry*; D001896:Boron Compounds / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D007700:Kinetics; D009154:Mutation; D009690:Nucleic Acid Conformation; D010100:Oxygen / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D019380:Anti-HIV Agents; D001896:Boron Compounds; D010710:Phosphates; D054303:HIV Reverse Transcriptase; D001895:Boron; D010100:Oxygen