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Journal of Virology, December 2007, p. 13845-13851, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01184-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Binding Kinetics of Darunavir to Human Immunodeficiency Virus Type 1 Protease Explain the Potent Antiviral Activity and High Genetic Barrier{triangledown}

Inge Dierynck,* Mieke De Wit, Emmanuel Gustin, Inge Keuleers, Johan Vandersmissen, Sabine Hallenberger, and Kurt Hertogs

Tibotec BVBA, Mechelen, Belgium

Received 31 May 2007/ Accepted 30 September 2007

The high incidence of cross-resistance between human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs) limits their sequential use. This necessitates the development of PIs with a high genetic barrier and a broad spectrum of activity against PI-resistant HIV, such as tipranavir and darunavir (TMC114). We performed a surface plasmon resonance-based kinetic study to investigate the impact of PI resistance-associated mutations on the protease binding of five PIs used clinically: amprenavir, atazanavir, darunavir, lopinavir, and tipranavir. With wild-type protease, the binding affinity of darunavir was more than 100-fold higher than with the other PIs, due to a very slow dissociation rate. Consequently, the dissociative half-life of darunavir was much higher (>240 h) than that of the other PIs, including darunavir's structural analogue amprenavir. The influence of protease mutations on the binding kinetics was tested with five multidrug-resistant (MDR) proteases derived from clinical isolates harboring 10 to 14 PI resistance-associated mutations with a decreased susceptibility to various PIs. In general, all PIs bound to the MDR proteases with lower binding affinities, caused mainly by a faster dissociation rate. For amprenavir, atazanavir, lopinavir, and tipranavir, the decrease in affinity with MDR proteases resulted in reduced antiviral activity. For darunavir, however, a nearly 1,000-fold decrease in binding affinity did not translate into a weaker antiviral activity; a further decrease in affinity was required for the reduced antiviral effect. These observations provide a mechanistic explanation for darunavir's potent antiviral activity and high genetic barrier to the development of resistance.

* Corresponding author. Mailing address: Tibotec BVBA, Gen De Wittelaan L 11B 3, 2800 Mechelen, Belgium. Phone: 32 15 461229. Fax: 32 15 444374. E-mail: idierinc{at}tibbe.jnj.com

{triangledown} Published ahead of print on 10 October 2007.

Journal of Virology, December 2007, p. 13845-13851, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01184-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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