Swati S. More, PhD
Assistant Professor, Center for Drug Design (CDD)
Assistant Professor, Center for Drug Design (CDD)
PhD, University of Minnesota (Medicinal Chemistry), 2007
BTech, University of Mumbai (Pharmaceuticals and Fine Chemicals), 2002
Research in my laboratories seeks to identify, describe and solve biological problems through chemical means. Improved understanding of the molecular bases of various pathological and toxicological phenomena are regarded as milestones, with the design and successful development of novel chemical or biological therapeutics and diagnostic tools being the end-goals. A broad range of techniques are employed toward these ends, ranging from animal behavior studies, molecular biology, organic synthesis, rational drug design, biophysics, imaging and microscopy. A keen emphasis is placed on inculcating interdisciplinary research skills in laboratory personnel that would enable them to function as independent researchers.
Currently targeted areas are:
1. Oxidative stress – pathological and toxicological studies, chemoprevention, drug design.
Amyloidogenic peptides are established etiological agents of Alzheimer’s and Parkinson’s diseases. We have shown through biophysical and biochemical investigations that the food additive, 2,3-butanedione (diacetyl) is capable of inducing amyloid peptide misfolding in intact cells. Ongoing research seeks to define the relevance of this phenomenon in the intact animal.
The human body utilizes glutathione (1) as a primary cellular reductant. This thiol has been shown to be depleted in conditions of oxidative damage. Administration of 1 does not lead to the latter’s intact passage to the site of action due to metabolic breakdown by ?-glutamyl transpeptidase. About five decades ago, Prof. Vince envisioned the creation of ?-GSH (2) as a means to bypass ?-glutamyl transpeptidase. We have now shown that 2 fulfills cardinal functions of 1, establishing it as a candidate for the treatment of a variety of conditions that involve deficiency of 1 and/or oxidative damage.
2. Drug transport – membrane transporters and their targeting.
The selective localization of membrane bound transport proteins renders attractive the latter’s exploitation for targeted drug delivery. Consequently, we are examining the distribution of membrane transporters in the body through various diagnostic probes and are designing small molecules that would be selectively uptaken by the transporter in question.
3. Imaging and diagnostic tool development.
We are seeking to validate imaging techniques for the identification and measurement of amyloidogenesis.
- Vince, R.; More, S. S. (2013) Hyperspectral imaging for early detection of Alzheimer’s disease. PCT Int. Appl. WO 2013086516 A1 20130613.
- Giacomini, K. M.; More, S. S. (2013) Preparation of platinum(II) chloro ammine complexes with piperazine as anticancer agents. PCT Int. Appl. WO 2013033041 A1 20130307.
- Vince, R.; More, S. S. (2013) Glutathione analogs for treating neurodegenerative disorders. PCT Int. Appl. WO 2013009647 A1 20130117.
- Vartak, A. P.; More, S. S.; Vince, R. Could the artificial butter flavoring, diacetyl, cause Alzheimer’s disease. Neurodegenerative Disease Management, 2012, 2: 1-3.
- More, S. S.; Vartak, A. P.; Vince, R. Restoration of Glyoxalase Enzyme Activity Precludes Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease. ACS Chemical Neuroscience, 2013, 4: 330-8.
- More, S. S.; Vartak, A. P.; Vince, R. The Butter Flavorant, Diacetyl, Exacerbates ?-Amyloid Cytotoxicity. Chemical Research in Toxicology, 2012, 25: 2083-91.
- Urscher, M.; More, S. S.; Alisch, R.; Vince, R.; Deponte, M. Tight-binding inhibitors efficiently inactivate both reaction centers of monomeric plasmodium falciparum glyoxalase 1. FEBS Journal, 2012, 279: 2568-78.
- More, S. S.; Raza, A.; Vince, R. The Butter Flavorant, Diacetyl, Forms a Covalent Adduct with 2-Deoxyguanosine, Uncoils DNA and Leads to Cell Death. Journal of Agricultural and Food Chemistry, 2012, 60: 3311-17.
- More, S. S.; Vince, R. Potential of a ?-glutamyl-transpeptidase-stable glutathione analogue against amyloid-? toxicity.ACS Chemical Neuroscience, 2012, 3: 204-10.
- More, S. S.; Itsara, M.; Yang, X.; Geier, E. G.; Tadano, M. K.; Seo, Y.; VanBrocklin, H. F.; Weiss, W. A.; Mueller, S.; Haas-Kogan, D. A.; DuBois, S. G.; Matthay, K. K.; Giacomini, K. M. Vorinostat increases expression of functional norepinephrine transporter in neuroblastoma in vitro and in vivo model systems. Clinical Cancer Research, 2011, 17: 2339-49.
- Li, S.; Chen, Y.; Zhang, S.; More, S. S.; Huang, X.; Giacomini, KM. Role of Organic Cation Transporter 1, OCT1 in the Pharmacokinetics and Toxicity of cis-Diammine(pyridine)chloroplatinum(II) and Oxaliplatin in Mice. Pharmaceutical Research, 2011, 28: 610-25.
- Chen, L.; Pawlikowski, B.; Schlessinger, A.; More, S. S.; Stryke, D.; Johns, S. J.; Portman, M. A.; Chen, E.; Ferrin, T. E.; Sali, A.; Giacomini, K. M. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenetics and Genomics, 2010, 20: 687-99.
- More, S. S.; Akil, O.; Ianculescu, A. G.; Geier, E. G.; Lustig, L. R.; Giacomini, K. M. Role of the copper transporter, CTR1, in platinum-induced ototoxicity. Journal of Neuroscience, 2010, 30: 9500-9.
- More, S. S.; Li, S.; Yee, S. W.; Chen, L.; Xu, Z.; Jablons, D. M.; Giacomini, K. M. Organic cation transporters modulate the uptake and cytotoxicity of picoplatin, a third-generation platinum analogue. Molecular Cancer Therapeutics, 2010; 9: 1058-69.
- More, S. S.; Vince, R. Inhibition of Glyoxalase-I: The First Low-Nanomolar Tight-Binding Inhibitors. Journal of Medicinal Chemistry, 2009, 52: 4650-6.
- More, S. S.; Vince, R. Design, Synthesis and Biological Evaluation of Glutathione Peptidomimetics as Components of Antiparkinson Prodrugs. Journal of Medicinal Chemistry, 2008, 51: 4581?8.
- Cropp, C. D.; Komori, T.; Shima, J. E.; Urban, T. J.; Yee, S. W.; More, S. S.; Giacomini, K. M. Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Molecular Pharmacology, 2008, 73: 1151–8.
- More, S. S.; Vince, R. Design, Synthesis and Binding Studies of Bidentate Zn-chelating Peptidic Inhibitors of Glyoxalase-I. Bioorganic and Medicinal Chemistry Letters, 2007, 17: 2793-7.
- More, S. S.; Vince, R. A Metabolically Stable Tight-binding Transition-state Inhibitor of Glyoxalase- I. Bioorganic and Medicinal Chemistry Letters, 2006, 16: 6039-42.