Abstract
HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs) , based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of structure-based drug design. The introduction of first-generation PIs marked the start of combination antiretroviral therapy . However, low bioavailability, high pill burden, and toxicity ultimately reduced adherence and limited long-term viral inhibition. Therapy failure was often associated with multiple protease inhibitor resistance mutations, both in the viral protease and its substrate (HIV gag protein), displaying a broad spectrum of resistance mechanisms. Unfortunately, selection of protease inhibitor resistance mutations often resulted in cross-resistance to other PIs.
Therefore, second-generation approaches were imperative. Coadministration of a cytochrome P-450 3A4 inhibitor greatly improved the plasma concentration of PIs in the patient. A second advance was the development of PIs that were efficacious against first-generation PI-resistant HIV. Both approaches increased the number of protease mutations required by the virus to develop clinically relevant resistance, thereby raising the genetic barrier towards PI resistance. These improvements greatly contributed to the success of PI-based therapy.
Keywords
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Acknowledgements
We thank Dr. Pavlina Rezacova from the Institute of Organic Chemistry and Biochemistry Institute of Molecular Genetics in Prague, Czech Republic, for preparing Fig. 3. Funding resource: the Netherlands Organization for Scientific Research (NWO) VIDI Grant (91796349).
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Wensing, A.M.J., Fun, A., Nijhuis, M. (2017). HIV Protease Inhibitor Resistance. In: Berghuis, A., Matlashewski, G., Wainberg, M., Sheppard, D. (eds) Handbook of Antimicrobial Resistance. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0694-9_28
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