Herbert Newby McCoy Award
2015 McCoy Award Recipient
Arun K. Ghosh – 2015 Herbert Newby McCoy Award
Arun K. Ghosh is the Ian P. Rothwell Distinguished Professor of Chemistry, Medicinal Chemistry and Molecular Pharmacology at Purdue University. He received his BS and MS degrees in chemistry at the University of Calcutta (1979) and the Indian Institute of Technology (1981), Kanpur, respectively. He obtained his PhD (1985) from the University of Pittsburgh. He then pursued postdoctoral research at Harvard University (1985-1988). Professor Ghosh’s research interests include diverse areas of organic, bioorganic and medicinal chemistry with particular emphasis on organic synthesis and protein-structure-based design of biomolecules.
Professor Ghosh has been awarded the Chemical Research Society of India Medal (2012), NIH Merit Award (2011), IUPAC-Richter Prize in Medicinal Chemistry (2010), American Chemical Society’s Arthur C. Cope Senior Scholar Award (2010), ACS Robert Scarborough Excellence in Medicinal Chemistry Award (2008), and Novartis Chemistry Lectureship (2010-2011). He is a Fellow of the Royal Chemical Society, FRSC (2015) and a Fellow of American Association for the Advancement of Science, AAAS (2005).
He was a University Scholar, University of Illinois (1998-2001) and National Scholar, Government of India (1976-1981). He has been on the editorial advisory boards of numerous organic and medicinal chemistry international journals.
Ghosh has published over 285 scientific research papers. He is an inventor of over 50 U.S. patents and patent applications on inhibitors of HIV-1 protease, β-secretase, SARS and anti-cancer agents. He has published two books entitled, “Structure-based Design of Drugs and Other Bioactive Molecules—Tools and Strategies” (Wiley-VCH, 2014) and “Aspartic Acid Proteases as Therapeutic Targets” (Wiley-VCH, 2010).
Abstract of Lecture
Historically, nature has provided an incredible variety of structurally complex and biologically important molecules. Many of today’s medicines are obtained directly from these natural products or from their derivatives.
Our chemical syntheses of medicinally important natural products and exploration of their function brought a unique perspective to our team’s drug design using the protein X-ray structure as a guide. We sought to develop innovative molecular probes against proteins implicated in the pathogenesis of human diseases.
The treatment of patients with HIV/AIDS continues to be very challenging due to viral mutation and rapid emergence of drug resistance. Our research efforts promoting “backbone binding” led to the HIV protease inhibitor-based drug, darunavir, for the treatment for all HIV/AIDS patients, including patients harboring drug-resistant HIV.
Also, we have led the important groundwork for structure-based design of inhibitors of memapsin 2 (β-secretase), an exciting drugdesign target for the treatment of Alzheimer’s disease. A number of potent and selective inhibitors from our laboratories show potential for clinical development. This presentation will feature novel design concepts, general strategies and development tools for HIV-1 protease inhibitors against HIV/AIDS and β-secretase inhibitors against Alzheimer’s disease.
Research Accomplishments
Professor Ghosh is one of the world’s leading authorities in protein X-ray structurebased molecular design. He has been designing innovative molecular scaffolds and templates by drawing inspiration from nature.
Ghosh developed the “backbone binding” concept for designing HIV protease inhibitors to combat drug resistance. He conceptualized that a molecule that maximizes interactions, particularly hydrogen bonding interactions with backbone atoms would likely conserve these interactions with mutant proteases, since the active site backbone conformation of mutant proteases is minimally distorted.
His laboratory has created a range of novel inhibitors that grasp the enzyme’s backbone like a “molecular crab.” Darunavir was designed to maintain antiviral activity against a wide spectrum of drug-resistant HIV-1 variants. Darunavir received FDA approval in 2006 as the first treatment for patients harboring multidrug-resistant HIV. In 2008, it was approved as first-line therapy for all HIV/AIDS patients including pediatrics. Darunavir’s ability to delay the onset of drug-resistance has set new standards for HIV/AIDS treatment.
Ghosh also has pioneered the design and synthesis of inhibitors of β-secretase or memapsin 2 (BACE), a key enzyme responsible for plaque production in the brain leading to Alzheimer’s disease (AD). Ghosh designed the first substrate-based β-secretase inhibitor, determined the first X-ray crystal structure of his inhibitor complexed with β-secretase, and established the X-ray structure-based evolution of nonpeptide inhibitors. His laboratory designed inhibitors with remarkable selectivity over other physiologically important enzymes.
Many inhibitors have been shown to penetrate the blood-brain barrier, inhibit plaque production in the brain of AD mice and rescue their cognitive decline. The work from Ghosh’s laboratories set the groundwork for tools and strategies for BACE inhibitors. A number of BACE inhibitors from other laboratories are now in advanced clinical development, showing potential for a disease-modifying treatment for Alzheimer’s disease.
Ghosh developed a range of cysteine protease inhibitors against SARS-CoV & MERS-CoV coronavirus proteases. He directed the design and development of a number of potent nonpeptide inhibitors for SARS-CoV 3CLpro (3C-like protease) and SARS-CoV PLpro (papain-like protease). This work on PLpro provided a first proof-of-principle that it is a viable target for development of antivirals directed against the SARS & MERS virus.
Ghosh’s synthesis and exploration of biology of natural products is extensive, including more than three-dozen structurally diverse families. Laulimalide and pelorusides are sponge-derived macrolides isolated in only miniscule quantities. Following laboratory syntheses of these natural products, Ghosh’s collaborative studies discovered that these drugs stabilize microtubules by binding at a previously unknown drug-binding site. In addition, laulimalide and peloruside were able to enhance tubulin ssembly synergistically with paclitaxel.
Ghosh also synthesized lasonolide, leading to elucidation of its mechanism of action for anti-tumor activity. He also synthesized potent spliceosome inhibitors, herboxidienes, pladienolide and pliceostatins, and established critical structure-activity studies. This has set the stage for the design of less complex spliceosome inhibitor-based anti-cancer drug development.
In the context of chemical syntheses, Ghosh has developed new and practical chemistry for asymmetric carbon-carbon and carbon-heteroatom bond forming reactions. These methods have been extensively employed in the synthesis of bioactive targets.
