Piyusha Pagare

Research Scholar - Medicinal Chemist

Piyusha Pagare

Lab Phone

+1 646 888 2238

Education:

PhD, Medicinal Chemistry, Virginia Commonwealth University, May 2018

M.Sc., Organic Chemistry, Mumbai University, 2012

B.Sc., Chemistry, Mumbai University, 2009

I received my PhD in Medicinal Chemistry at the Virginia Commonwealth University under the supervision of Drs. Yan Zhang and Martin Safo. My PhD work combined structure-based drug design, including X-ray crystallography and molecular modeling to synthesize and biologically evaluate allosteric modulators of hemoglobin for the treatment of sickle cell disease. Sickle cell disease is a hereditary blood disorder wherein a mutation in hemoglobin (Hb) causes deoxygenated sickle Hb to form insoluble polymers that give rise to rigid sickle shaped red blood cells (RBCs) that occlude the capillaries and blood vessels. Dr. Safo’s lab has been instrumental in developing covalent modifiers of hemoglobin that inhibit RBC sickling by increasing the oxygen affinity of Hb. However, challenges related to short half-life have severely hampered this line of investigation. To counter these challenges, I designed and synthesized a series of small molecules followed by their in vitro investigations to ascertain sustained binding, modification of Hb and sickling inhibition. Further, I conducted x-ray crystallography studies to establish their mode of interaction with Hb. These results led to the development of highly potent allosteric modulators of hemoglobin that are currently being studied in vivo.

I joined Dr. Chiosis lab as a research scholar in 2018. Here, my project is aimed towards the design, synthesis and biological characterization of potent and selective inhibitors of hyperglycosylated Glucose Regulated Protein 94 (hgGRP94). GRP94 is a chaperone protein that plays an important role in protein folding and maintaining ER quality. GRP94, however, has been shown to be important for tumor survival and helps regulate the stability of plasma membrane-bound RTKs to maintain their oncogenic properties. Previously, the Chiosis lab has shown that specific inhibition of hgGRP94 is feasible in cancer and have identified a series of highly selective ligands. The goal of my project is to advance these ligands to clinical leads that target hgGRP94 and identify those tumors sensitive to inhibition. Towards this, with the aid of structure-based drug design, a library of small molecules will be synthesized and characterized using various in vitro assays with promising candidates leading to in vivo studies. During my postdoctoral training here, I expect to advance my synthetic and medicinal chemistry skills as well as gain experience in various biological techniques.

 

 

Publications


  1. Pagare, P. P.; Wang, H.; Wang, X. Y.; Zhang, Y. Understanding the role of glucose regulatedprotein 170 (GRP170) as a nucleotide exchange factor through molecular simulations. J. Mol. Graph. Model. 201885, 160-170.

  2. Deshpande, T.M.; Pagare, P.P.; Ghatge, M.S.; Chen, Q.; Musayev, F.N.; Venitz, J.; Zhang, Y.; Abdulmalik, O.; Safo, M.K. Rational modification of vanillin derivatives to stereospecifically destabilize sickle hemoglobin polymer formation. Acta Cryst. D 2018,74, 956-94.

  3. Pagare, P. P.; Ghatge, M.S.; Musayev, F.N.; Deshpande, T.M.; Chen, Q.; Braxton, C.; Kim, S.; Venitz, J.; Zhang, Y.; Abdulmalik, O.; Safo, M.K. Rational design of pyridyl derivatives of vanillin for the treatment of sickle cell disease.Bioorg. Med. Chem. 201826, 2530-2538.

  4. Xu, G.G.; Pagare, P.P.; Ghatge, M.S.; Safo, R.P.; Gazi, A.; Chen, Q.; David, T.; Alabbas, A.B.; Musayev, F.N.; Venitz, J.; Zhang, Y.; Safo, M.K.; Abdulmalik, O. Design, synthesis and biological evaluation of ester and ether derivatives of antisickling agent 5-HMF for the treatment of sickle cell disease. Mol. Pharm.2017,14, 3499-3511.

  5. Pagare, P.P.; Zaidi, S.A.; Zhang, X.; Li, X.; Yu, X.; Wang, X.Y.; Zhang, Y. Understanding molecular interactions between scavenger receptor A and its natural product inhibitors through molecular modeling studies.  J. Mol. Graph. Model. 201777, 189-199. 

  6. Zheng, Y.; Li, X.; Pagare, P.P.; Yuan, Y.; Wang, X.Y.; Zhang, Y. Design, synthesis, and characterization of rhein analogs as novel inhibitors of scavenger receptor A. Bioorg. Med. Chem. Lett. 201727, 72-76.

  7. Ghatge, M.S.; Ahmed, M.H.; Omar, A.M.;Pagare, P.P.; Rosef, S.; Kellogg, G. E.; Abdulmalik, O.; Safo, M.K. Crystal structure ofcarbonmonoxy hemoglobin in R-state conformation. J. Struct. Biol. 2016194, 446-450.