Introduction to Biological and Small Molecule Drug Research and Development: Chapter 13. Design of the anti-HIV protease inhibitor darunavir

Introduction to Biological and Small Molecule Drug Research and Development: Chapter 13. Design of the anti-HIV protease inhibitor darunavir
ISBN-10
0128062037
ISBN-13
9780128062036
Series
Introduction to Biological and Small Molecule Drug Research and Development
Category
Science
Pages
472
Language
English
Published
2013-05-07
Publisher
Elsevier Inc. Chapters
Authors
Arun K. Ghosh, Bruno D. Chapsal

Description

The development of HIV protease inhibitors (PIs) and their inclusion in highly active antiretroviral therapies (HAARTs) marked the beginning of a treatment breakthrough in the management of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The HAART treatment regimen can cut HIV viral load to undetectable levels. Nonetheless, the rapid emergence of HIV drug resistance has continued to seriously compromise long-term treatment options for HIV-infected patients. Our structure-based design strategy to develop PIs that specifically target the enzyme's backbone atoms has resulted in a number of very potent inhibitors with superior drug resistance profiles. Of particular note, our development of stereochemically defined bis(tetrahydrofuranyl) urethane as a high-affinity P2 ligand has led to the development of exceedingly potent inhibitors. One of these inhibitors, darunavir, has shown exceptional potency against the HIV-1 virus and superior activity against multi-PI-resistant viral strains. Our backbone binding strategy was corroborated with detailed crystal structure analyses of darunavir-bound protease complexes which revealed a series of conserved interactions between the inhibitor and key backbone atoms of HIV-1 protease. Darunavir first received accelerated US Food and Drug Administration approval in 2006 for highly treatment-experienced patients with little therapeutic options. It has now become a leading PI in the fight against HIV infection and drug resistance.

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