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Journal of Virology, December 2006, p. 12283-12292, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.00889-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Indolopyridones Inhibit Human Immunodeficiency Virus Reverse Transcriptase with a Novel Mechanism of Action{triangledown}

Dirk Jochmans,1* Jérôme Deval,2 Bart Kesteleyn,1 Herwig Van Marck,1 Eva Bettens,1 Inky De Baere,1 Pascale Dehertogh,1 Tania Ivens,1 Marcia Van Ginderen,1 Bertrand Van Schoubroeck,1 Maryam Ehteshami,2 Piet Wigerinck,1 Matthias Götte,2 and Kurt Hertogs1

Tibotec BVBA, Generaal De Wittelaan L 11B 3, 2800 Mechelen, Belgium,1 Department of Microbiology and Immunology, McGill University, Duff Medical Building (D-6), 3755 University Street, Montreal, Quebec H3A 2B4, Canada2

Received 2 May 2006/ Accepted 26 September 2006

We have discovered a novel class of human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors that block the polymerization reaction in a mode distinct from those of the nucleoside or nucleotide RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). For this class of indolopyridone compounds, steady-state kinetics revealed competitive inhibition with respect to the nucleotide substrate. Despite substantial structural differences with classical chain terminators or natural nucleotides, these data suggest that the nucleotide binding site of HIV RT may accommodate this novel class of RT inhibitors. To test this hypothesis, we have studied the mechanism of action of the prototype compound indolopyridone-1 (INDOPY-1) using a variety of complementary biochemical tools. Time course experiments with heteropolymeric templates showed "hot spots" for inhibition following the incorporation of pyrimidines (T>C). Moreover, binding studies and site-specific footprinting experiments revealed that INDOPY-1 traps the complex in the posttranslocational state, preventing binding and incorporation of the next complementary nucleotide. The novel mode of action translates into a unique resistance profile. While INDOPY-1 susceptibility is unaffected by mutations associated with NNRTI or multidrug NRTI resistance, mutations M184V and Y115F are associated with decreased susceptibility, and mutation K65R confers hypersusceptibility to INDOPY-1. This resistance profile provides additional evidence for active site binding. In conclusion, this class of indolopyridones can occupy the nucleotide binding site of HIV RT by forming a stable ternary complex whose stability is mainly dependent on the nature of the primer 3' end.

* Corresponding author. Mailing address: Tibotec BVBA, Generaal De Wittelaan L 11B 3, 2800 Mechelen, Belgium. Phone: 32 15 401 208. Fax: 32 15 444 374. E-mail: djochman{at}tibbe.jnj.com.

{triangledown} Published ahead of print on 4 October 2006.

Journal of Virology, December 2006, p. 12283-12292, Vol. 80, No. 24
0022-538X/06/$08.00+0     doi:10.1128/JVI.00889-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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