XI International HIV Drug Resistance Workshop: Basic Principles and Clinical Implications


Seville, Spain, 2–5 July 2002


THE USE OF α-BORANOPHOSPHATE NUCLEOSIDE ANALOGUES TO SUPPRESS HIV-MEDIATED MULTI-DRUG RESISTANCE TO LAMIVUDINE, DIDEOXYNUCLEOSIDES, AND ZIDOVUDINE

Antivir Ther. 2002;7(Suppl 1):S8 (abstract no. 8)

J Deval1, B Selmi1, B Schneider2, P Meyer3, J Boretto1, S Sarfati3, D Deville- Bonne2, C Guerreiro3, J Janin3, M Véron2 and B Canard1
1Centre National de la Recherche Scientifique, Marseille, France ; 2Centre National de la Recherche Scientifique, Paris, France; 3Centre National de la Recherche Scientifique and Institut Pasteur, Paris, France

Combination therapy using 3'-azido-3'deoxythymidine (AZT), lamivudine (3TC), and dideoxynucleosides (ddNs) is the method of choice to control HIV, but the appearance of multidrug nucleoside resistance (MDNR) is reducing the efficiency of chemotherapies. We have elucidated the molecular basis of resistance for number of multidrug-resistant reverse transcriptases (RTs) at the molecular level provided the K65R, Q151M complex, and M184V substitutions. We have previously described the synthesis and the improved NDPK-mediated activation of AZTTP and ddNTP analogues with a borano (BH3–) group on the α-phosphate (Meyer, P, Schneider B, Sarfati S, Deville- Bonne D, Guerreiro C, Boretto J, Janin J, Véron M & Canard, B. "Structural basis for activation of α-boranophosphate nucleotide analogues targeting drug resistant reverse transcriptase". EMBO J. 2000 Jul 17;19(14):3520-9). We extend now this work to BH3–– 3TCTP, and describe in molecular terms the use of BH3–– AZTTP, of BH3–– ddATP, and BH3–– 3TCTP to suppress resistance mediated by the K65R, Q151M complex, and M184V RTs, respectively (Selmi B, Boretto J, Sarfati SR, Guerreiro C, Canard B. "Mechanism-based suppression of dideoxynucleotide resistance by K65R human immunodeficiency virus reverse transcriptase using an α-boranophosphate nucleoside analogue". J Biol Chem. 2001 Dec 21;276(51):48466-72). These high levels of resistance are the result of a severe drop of polymerization rate (kpol) related to the wild-type enzyme. The low incorporation rates were greatly increased using α-boranophosphate nucleotide analogues on MDNR reverse transcriptase. In all cases, the presence of the BH3–– group is able to completely reverse a resistance, renderering such multi-drug resistant RT as sensitive to chain-termination as wildtype RT. Kpol values are increased up to 150-fold with these analogues, emphasizing the capacity of such analogues to restore MDNR mutant sensitivity in vitro. Knowledge of the exact mechanism of drug resistance and suppression will guide design of novel nucleotide analogues, such as PMPA, for which both the K65R substitution and the borano substitution might prove very relevant in future therapies.

PRESENTING AUTHOR: B Canard

This work was supported by a grant from the Agence Nationale de la Recherche sur le Sida, the Agence de la Recherche sur le Cancer, and Ensemble contre le Sida.

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