13th International HIV Drug Resistance Workshop


8–12 June 2004, Tenerife Sur-Costa Adeje, Canary Islands, Spain


DIOXOLANE-THYMINE NUCLEOSIDE (DOT) AGAINST DRUG-RESISTANT HIV-1 MUTANTS AND ITS MOLECULAR MECHANISM

Antiviral Therapy 2004; 9:S21

CK Chu1, YH Chong1 and RF Schinazi2
1The University of Georgia College of Pharmacy, Athens, Ga., USA; and 2Emory University School of Medicine/VA Medical Center, Decatur, Ga., USA

BACKGROUND: The majority of AIDS patients are currently taking nucleosides as part of a combination therapy. Therefore, the development of nucleoside-resistant mutants of HIV-1 is a serious problem for the management of HIV infection.

METHODS: Since the discovery of βD-dioxolane-2,6- diaminopurine (DAPD or Amdoxovir) is active against AZT- and 3TC-resistant mutants, several other nucleosides with a dioxolane moiety have been synthesized in our laboratories, and their anti-HIV activity against drug-sensitive and drug-resistant mutants was determined, and their molecular mechanisms have been studied by molecular modelling.

RESULTS: Among the series of dioxolane nucleosides, the thymidine (DOT) showed significant and interesting anti-HIV activity against nucleoside-resistant mutants, as shown below. It was found from the molecular modelling studies that the dioxolane moiety plays a significant role in stabilizing the binding between the mutant HIV RT and the nucleoside TP.

Resistance
strains		 EC50
(µg)		 IC50
(µg/ml)		 TI Activity
D67N, K70R, K103N, I135L, M184V, K219E, R284K, C355F, R356K 2.44 >100 >41 Active
M41L, E122K, M184V, T215Y 1.13 >100 >42 Active
M41L, D67N, K70R, T215Y, K219Q 0.29 >100 >345 Highly
active
Other mutations not associated with AZT/R=V60I, K83R, H208Y, L239V, R356K G359S
LAI M184V 0.29 >40 >137 Highly
active

CONCLUSIONS: DOT is significantly active against nucleoside-resistant HIV-1 mutants. Thus, additional biological studies are warranted to determine the full potential of DOT as a potential anti-HIV agent (Supported by NIH AI32351, AI25899 and Veterans Affairs).

PRESENTING AUTHOR: CK Chu

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2004-06-08
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