Acquired immunodeficiency syndrome (AIDS) is one of the most destructive epidemics in medical history. In 2009, the UNAIDS report estimated that 35 million people are living with human immunodeficiency virus (HIV) infection and AIDS, 25 million deaths have occurred, and 14 million children have been orphaned since the epidemic began in 1981. The discovery of HIV, the etiological agent for AIDS, led to the identification of a number of biochemical targets to combat this devastating disease. Among them, therapeutic inhibition of a proteolytic enzyme, HIV-1 protease, emerged as a critical drug-development target. Subsequent design and discovery of protease inhibitors (PIs) and their introduction into the highly active antiretroviral therapy (HAART), marked the beginning of a new era of management of HIV-1 infection and AIDS. HAART significantly improved the quality of life and life expectancy of patients. There is no cure for HIV/AIDS and long-term treatment has posed a serious challenge because of the emergence of multidrug-resistant HIV-1 variants. About 40-50% of those patients who initially achieved favorable viral suppression to undetectable levels experienced treatment failure. These drug-resistant HIV strains can be transmitted, raising further uncertainty with respect to future treatment options. In addition, PIs are faced with a number of serious limitations including, major toxicity, tolerance, and adherence to complex medical regimens. The development of a new generation of PIs effective against drug-resistant HIV and with minimum side effects, are vital to the future management of HIV/AIDS. Our collaborative research efforts to combat drug resistance, led to the development of darunavir which was first approved for treatment against drug-resistant HIV in June, 2006, and then received full approval for all HIV/AIDS patients including pediatric patients in December, 2008. While darunavir has become a front line therapy against HIV/AIDS, it is far from ideal as an effective long-term treatment option. During this project period, based upon X-ray crystal structures of complexes of darunavir or other PIs with HIV-1 protease, we designed and synthesized a diverse class of potent PIs with marked antiviral activity, and excellent drug-resistance profiles against multidrug-resistant HIV-1 strains. We have also developed tools and important 'backbone binding'design concepts to combat drug-resistance. Furthermore, we have discovered a number of small molecule nonpeptide structural leads for optimization. A recent inhibitor, GRL-0519, has consistently shown a 10-fold improvement of potency compared to darunavir against a panel of multidrug-resistant HIV-1 variants. This PI also exhibited 10-fold better dimerization inhibitory properties of HIV-1 protease. Our current proposed studies are now focused on design, synthesis, and evaluation of the next generation of PIs for clinical development. Our multidisciplinary research efforts integrate structure-based design, synthesis, protein-ligand X-ray crystallography, inhibition kinetics, molecular modeling, and in-depth virus and cell-biological studies.

Public Health Relevance

The 2010 UNAIDS reports 35 million people are living with HIV/AIDS (Acquired Immunodeficiency Syndrome). Progress against this global pandemic requires innovative improved treatment. This proposal details our design and synthesis of next generation protease inhibitors to address critical problems of existing therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM053386-18
Application #
8324992
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Fabian, Miles
Project Start
1996-04-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
18
Fiscal Year
2012
Total Cost
$358,713
Indirect Cost
$113,529
Name
Purdue University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Ghosh, Arun K; Keyes, Chad; Veitschegger, Anne M (2014) FeCl3-Catalyzed Tandem Prins and Friedel-Crafts Cyclization: A Highly Diastereoselective Route to Polycyclic Ring Structures. Tetrahedron Lett 55:4251-4254
Ghosh, Arun K; Lv, Kai (2014) A convergent synthesis of carbocyclic sinefungin and its C5 epimer. European J Org Chem 2014:6761-6768
Ghosh, Arun K; Schiltz, Gary E; Rusere, Linah N et al. (2014) Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1-P2 ligands. Org Biomol Chem 12:6842-54
Yedidi, Ravikiran S; Garimella, Harisha; Aoki, Manabu et al. (2014) A conserved hydrogen-bonding network of P2 bis-tetrahydrofuran-containing HIV-1 protease inhibitors (PIs) with a protease active-site amino acid backbone aids in their activity against PI-resistant HIV. Antimicrob Agents Chemother 58:3679-88
Hayashi, Hironori; Takamune, Nobutoki; Nirasawa, Takashi et al. (2014) Dimerization of HIV-1 protease occurs through two steps relating to the mechanism of protease dimerization inhibition by darunavir. Proc Natl Acad Sci U S A 111:12234-9
Ghosh, Arun K; Chen, Zhi-Hua (2014) An intramolecular cascade cyclization of 2-aryl indoles: efficient methods for the construction of 2,3-functionalized indolines and 3-indolinones. Org Biomol Chem 12:3567-71
Amano, Masayuki; Tojo, Yasushi; Salcedo-Gomez, Pedro Miguel et al. (2013) GRL-0519, a novel oxatricyclic ligand-containing nonpeptidic HIV-1 protease inhibitor (PI), potently suppresses replication of a wide spectrum of multi-PI-resistant HIV-1 variants in vitro. Antimicrob Agents Chemother 57:2036-46
Agniswamy, Johnson; Shen, Chen-Hsiang; Wang, Yuan-Fang et al. (2013) Extreme multidrug resistant HIV-1 protease with 20 mutations is resistant to novel protease inhibitors with P1'-pyrrolidinone or P2-tris-tetrahydrofuran. J Med Chem 56:4017-27
Zhang, Hongmei; Wang, Yuan-Fang; Shen, Chen-Hsiang et al. (2013) Novel P2 tris-tetrahydrofuran group in antiviral compound 1 (GRL-0519) fills the S2 binding pocket of selected mutants of HIV-1 protease. J Med Chem 56:1074-83
Ghosh, Arun K; Zhou, Bing (2013) Bifunctional cinchona alkaloid-squaramide-catalyzed highly enantioselective aza-Michael addition of indolines to *,*-unsaturated ketones. Tetrahedron Lett 54:3500-3502

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