4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

4′-DEAMINATED TSAO-T: PROTOTYPE OF A SECOND GENERATION OF TSAO NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR DERIVATIVES WITH A DIFFERENT RESISTANCE PROFILE

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):8 (Abstract 10

S Velázquez¹, E Lobatón¹, MJ Pérez-Pérez¹, E De Clercq², J Balzarini² and MJ Camarasa^1
1Instituto de Química Médica (C.S.I.C.), Madrid, Spain; and ²Rega Institute for Medical Research, Leuven, Belgium

INTRODUCTION: Among non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), TSAO derivatives occupy a unique position because they need to interact with the p51 subunit of the HIV-1 RT heterodimer. TSAO derivatives consistently select for 138-Lys mutated virus strains that are highly resistant to the inhibitory effect of TSAO. Our experimental data, together with molecular modelling studies, strongly suggest a specific interaction between the 138Glu of the p51 subunit of HIV-1 RT and the 4′-amino group of the 3′-spiro moiety of TSAO molecules.

OBJECTIVE: To obtain a second-generation TSAO derivative with a different resistance profile to the first generation of TSAO derivatives.

METHODS: Based on our hypothesis that a specific interaction exists between the 4′-amino group of TSAO-T and the Glu-138 of the p51 subunit, it was crucial to remove this amino group and evaluate the activity and resistance profile of the corresponding deaminated TSAO derivatives. The synthesis of a deaminated TSAO derivative was carried out by a radical deamination reaction of TSAO-m³T (the thymine prototype compound) with n-pentyl nitrite in THF. These mild, non-aqueous, non-acidic conditions allowed us to obtain the deaminated compound without deprotection of the acid- and base-sensitive t- BDMS groups of the TSAO molecules that are crucial for interaction with HIV-1 RT.

RESULTS: The new 4′-H TSAO-T compound proved inhibitory to HIV-1 replication in CEM cell culture (EC₅₀=0.15 μM) and in MT-4 (EC₅₀=0.53 μM). When resistant virus strains were selected in the presence of this new compound, mutant 138-Lys strains (TSAO-resistant) did not appear. Moreover, the resistant strains were fully sensitive to all clinically used nucleoside RT inhibitors and NNRTIs and also to the first-generation TSAO derivatives.

CONCLUSION: We have synthesized the first TSAO molecule that lacks the amino group at the 3′-spiro moiety. This deaminated TSAO molecule showed an aberrant resistance spectrum. It kept its HIV-1 specificity (NNRTI-characteristic) but did not select for any of the classical NNRTI-specific mutations in the NNRTI binding pocket. The mutations are not yet unambiguously determined. Also, the resistant viruses that emerged with the deaminated TSAO were only resistant to this drug and not to other NNRTIs, including any other TSAOs that contain the amino group on the spiro moiety. This opens interesting perspectives for the development of novel types of TSAO molecules that may be of use in combination therapies.

Download abstract

2000-06-12
10

Copyright © 2000 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the International Medical Press Ltd. 2-4 Idol Lane, London EC3R 5DD UK.