The Ghosh Laboratories:

The Home of the Backbone Binding, Bioactive Natural Product Synthesis, and Nature-Inspired Molecular Design for Today's Medicine

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Purdue University

 

Harnessing the Power of Organic Synthesis for Today's Medicine

In the Ghosh Research Labs, our graduate students and post-doctoral associates are utilizing the power of organic synthesis to address many challenging problems in today's medicine. Our research spans the areas of drug design and medicinal chemistry, natural product total synthesis, organometallic chemistry and new reaction development, to tackle diverse biological problems. We are located in the R. B. Wetherill Laboratory of Chemistry, a National Historic Chemical Landmark, on the Purdue University campus. 


FDA Approved Darunavir and GRL-142's Exceptional Promise

In 2006, Darunvir received accelerated approval for HIV/AIDS patients harboring multidrug-resistant HIV-1 variants.  In 2008, darunavir received full approval for both treatment-naive and treatment-experienced HIV/AIDS patients. Darunavir is currently approved in over 80 countries and is used as first-line therapy. Our recently developed protease inhibitor GRL-142 is showing exceptional properties.


Natural Product Synthesis and Anticancer Drug Development

We are exploring chemistry and biology of natural products. We have synthesized numerous rare and medicinally important natural products covering several dozen structural families. Our in-depth biological studies led to the discovery of new and exciting targets for anticancer drug development. These include laulimalide and peloruside as novel microtubule stabilizing agents, Lasonalide as RAFI kinase activator and spliceostatin, pladienolide and herboxidiene as novel spliceosome inhibitors.


BACE Inhibitors' Clinical Trials for Alzheimer's Disease

BACE1 (β-secretase, memapsin 2) is a promising drug-development target for Alzheimer’s Disease. Since its identification in 2000, our labs pioneered the structure-based design of BACE inhibitors. We developed tools and strategies for molecular design and created many early inhibitors covering different structural classes. Inhibitor drug GRL-8234 rescues cognitive decline in transgenic mouse models for Alzheimer's disease. Several BACE inhibitors from pharma labs are in advanced clinical trials.

 

Recent Publications

  • “Exploration of P1 and P4 Modifications of Nirmatrelvir: Design, Synthesis, Biological Evaluation, and X-ray Structural Studies of SARS-CoV-2 Mpro Inhibitors”  A. K. Ghosh, M. Yadav, S. Iddum, S. Ghazi, U. Jayashankar, S. N. Beechboard, Y. Takamatsu, S.- i. Hattori, M. Amano, N. Higashi-Kuwata, H. Mitsuya, A. D. Mesecar, Eur. J. Med. Chem. 2024, 116132.

  • “Development of a new class of potent and highly selective G protein-coupled receptor kinase 5 inhibitors and structural insight from crystal structures of inhibitor complexes,”  Y. Chen, A. Sonawane, R. Manda, R. K. Gadi, J. J. G. Tesmer, A. K. Ghosh, Eur. J. Med. Chem. 2024, 115931.

  • “An Enzymatic Route to the Synthesis of Tricyclic Fused Hexahydrofuranofuran P2-Ligand for a Series of Highly Potent HIV-1 Protease Inhibitors,”  A. K. Ghosh, A. Sharma, S. Ghazi, Tetrahedron Letters. 2024, 155013.

  • "Total Synthesis of Neuroprotective Agents, (+)-Lycibarbarine A and (-)-Lycibarbarine B," A. K. Ghosh, M. Harper, W. Robinson, J. Org. Chem. 2023, 88, 9530–9536.

  • "Synthesis of Optically Active SARS-CoV-2 Mpro inhibitor drug Nirmatrelvir (Paxlovid): an Approved Treatment of COVID-19,"  A. K. Ghosh, M. Yadav, Org. Bimol. Chem. 2023, 21, 5768-5774.

  • "SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads," A. K. Ghosh, D. Shahabi, M. E. C. Imhoff, S. Kovela,  A. Sharma, S.- i. Hattori, N. Higashi-Kuwata, H. Mitsuya, A. D. Mesecar, Bioorg. & Med. Chem. Lett. 2023, 129489.

  •  "GRL-142 binds to and impairs HIV-1 integrase nuclear localization signal and potently suppresses highly INSTI-resistant HIV-1 variants," M. Aoki, H. Aoki-Ogata, H. Bulut , H. Hayashi, N. Takamune, N. Kishimoto, H. Tanaka, N. Higashi-Kuwata, S. Hattori, D. Das, K. V. Rao, K. Iwama, D. A. Davis, K. Hasegawa, K. Murayama, R. Yarchoan, A. K. Ghosh, A. K. Pau, S. Machida, S. Misumi, H. Mitsuya, Science Adv. 2023, 9, eadg2955.

  • "Exploration of Imatinib and Dasatinib-derived Templates as the P2-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation," A. K. Ghosh,  J. L. Mishevich, S. Kovela, R. Shaktah, A. K. Ghosh, M. Johnson, Y.-F. Wang, A. Wong-Sam, J. Agniswamy, M. Amano, Y. Takamatsu, S. Hattori, I. T. Weber, H. Mitsuya, E. J. Med. Chem. 2023, 255, 115385.

  • "Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies," A. K. Ghosh, D. Shahabi, M. Kipfmiller, A. K. Ghosh, M. Johnson, Y.-F. Wang, J. Agniswamy, M. Amano, I. T. Weber, H. Mitsuya, Bioorg. & Med. Chem. Lett. 2023, 83, 129168.

  • "Four decades of continuing innovations in the development of antiretroviral therapy for HIV/AIDS: Progress to date and future challenges," A. K. Ghosh, Global Health & Medicine. 2023, 5, 194-198.

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