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Introduction to Biological and Small Molecule Drug Research and Development
Arun K. GhoshBruno D. Chapsal
其他書名
Chapter 13. Design of the anti-HIV protease inhibitor darunavir
出版Elsevier Inc. Chapters, 2013-05-07
主題Science / Chemistry / OrganicScience / Chemistry / Industrial & TechnicalTechnology & Engineering / Chemical & Biochemical
ISBN01280620379780128062036
URLhttp://books.google.com.hk/books?id=yUJ2DAAAQBAJ&hl=&source=gbs_api
EBookSAMPLE
註釋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.