Laboratory of Umesh R. Desai, Ph.D.
Our major contribution to science has been designing ‘new therapeutic agents’. We work in the area of designing glycosaminoglycans (GAGs) and non-saccharide GAG mimetics (NSGMs) that possess potent, selective biological activity. We are the rare medicinal chemistry group that is attempting to translate fundamental discoveries on GAG–protein interactions into molecules with potentially clinical benefit. Our work has led to the design of sulfated benzofurans and sulfated glucopyranosides as antithrombotic agents; sulfated bi-flavonoids as anti-cancer agents, and sulfated low molecular weight lignins as anti-emphysema agents. On the ‘tools’ level, our lab has developed: 1) combinatorial virtual library screening (CVLS) technology for identifying ‘high-affinity, high-specificity’ GAG and NSGM agents; 2) microwave-based sulfation approach for synthesis of sulfated GAGs and NSGMs; 3) drug design strategy for discovering allosteric inhibitors of GAG-binding proteins (coagulation factors, growth factors, chemokines, etc); and 4) chemical biology- and mass spectrometry-based techniques for studying interaction of GAGs and NSGMs with proteins. This body of work has led to the discovery of promising GAG/NSGM-based agents for development as drugs in the areas of cancer, thrombosis, emphysema and cystic fibrosis.
Of particular interest to cancer, we collaborate with Prof. Bhaumik Patel of McGuire VA Medical Center and Massey Cancer Center. The fundamental idea exploited in our work is that GAGs modulate a large number proteins involved in cell growth, cell renewal, differentiation, inflammation and immune response. More specifically, a specific GAG called heparan sulfate (HS) interacts with many growth factors, chemokines, etc. modulates intracellular signaling. Our central hypothesis has been that it should be possible to discover new anti-cancer therapeutics by aiding or interfering with GAG–protein interactions of relevance to cancer. Screening a library of synthetic GAG mimetics called NSGMs against cancer cells grown under spheroid and monolayer conditions identified a small group of agents that preferentially target cancer stem cells. These new chemical entities have been further studied in several models of cancer in which CSCs play important roles under in vitro (cell lines and organoids) as well as in vivo (rodents) conditions.
Morla, S.; Sankaranarayanan, NV.; Afosah, D. K.; Kumar, M.; Kummarapurugu, A. B.; Voynow, J. A.; Desai, U. R.* On the process of discovering leads that target the heparin-binding site of neutrophil elastase in the sputum of cystic fibrosis patients. Journal of Medicinal Chemistry 2019, (in press). (PMID: 31074986)
Nagarajan, B.; Sankaranarayanan, NV.; Desai, U. R.* A perspective on computational simulations of glycosaminoglycans. WIREs Computational Molecular Science 2019, 9, e1388. (PMID: 31080520)
Boothello, R. S.; Patel, N. J.; Sharon, C.; Abdelfadiel, E. I.; Morla, S.; Brophy, D. B.; Lippmann, R. H.; Desai, U. R.;* Patel, B. B.* A unique non-saccharide mimetic of heparin hexasaccharide selectively inhibits cancerous but protects adult colonic stem/progenitor cells via a common mechanism of induction of p38 mitogen-activated protein kinase. Molecular Cancer Therapeutics 2019, 18, 51–63. (PMID: 30337351)
Majmudar, H.; Hao, M.; Sankaranarayanan, NV.; Zanotti, B.; Volin, M. V.; Desai, U. R.; Tiwari, V.* A synthetic glycosaminoglycan mimetic blocks HSV-1 infection in human iris stromal cells. Antiviral Research 2019, 161, 154 – 162.