Swati S. More, PhD

Research Summary

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.

Research Projects

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 as a primary cellular reductant. This thiol has been shown to be depleted in conditions of oxidative damage. Administration of glutathione 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 ?-glutathione (?-GSH) as a means to bypass ?-glutamyl transpeptidase. We have now shown that ?-GSH fulfills cardinal functions of glutathione, establishing it as a candidate for the treatment of a variety of conditions that involve deficiency of glutathione 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.

• Singh, R.; Xie, W.; Williams, J.; Vince, R.; More, S. S. Discovery of anticancer clinical candidate, tosedostat, as an analgesic agent. ACS Chemical Neuroscience. 2019,10, 4007-4017 (Abstract)
• More, S. S.; Nugent, J.; Vartak, A. P.; Nye, Steffan M.; Vince, R. Hepatoprotective effect of ?-Glutathione in a murine model of acetaminophen-induced liver toxicity. Chemical Research in Toxicology. 2017, 30: 777-784 (Abstract). 
• More, S. S.; Beach, J. M.; Vince, R. Early detection of amyloidopathy in Alzheimer's mice by hyperspectral endoscopy. Investigative Ophthalmology and Visual Science. 2016, 57: 3231-3238 (Abstract).
• Ai, T.; Wilson D. J.; More, S. S.; Xie, J.; Chen, L. 5-((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors. Journal of Medicinal Chemistry, 2016, 59: 2928-2941.
• Wezena, C. A.; Urscher, M.; Vince, R.; More, S. S.; Deponte, M. Hemolytic and antimalarial effects of tight-binding glyoxalase 1 inhibitors on the host-parasite unit of erythrocytes infected with Plasmodium falciparum. Redox Biology, 2016, 8: 348-353.
• More, S. S.; Vince, R. Hyperspectral Imaging Signatures Detect Amyloidopathy in Alzheimer’s Mouse Retina Well Before Onset of Cognitive Decline ACS Chemical Neuroscience, 2015, 6, 306-315 (Abstract)
• Cui, H.; Kamal, Z.; Ai, T.; Xu, Y.; More, S. S.; Wilson, D.; Chen, L. Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach. Journal of Medicinal Chemistry, 2014, 57: 8340-8357.
• 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: 330-338.
• More, S. S.; Vartak, A. P.; Vince, R. The Butter Flavorant, Diacetyl, Exacerbates ?-Amyloid Cytotoxicity. Chemical Research in Toxicology, 2012, 25: 2083-2091.
• 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: 2568-2578.
• 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: 3311-3317.
• More, S. S.; Vince, R. Potential of a b-glutamyl-transpeptidase-stable glutathione analogue against amyloid-b toxicity.ACS Chemical Neuroscience, 2012, 3: 204-210.
• 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: 2339-2249.
• 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: 610-625.
• 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: 687-699.
• 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: 9500-9509.
• 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: 1058-1069.
• More, S. S.; Vince, R. Inhibition of Glyoxalase-I: The First Low-Nanomolar Tight-Binding Inhibitors. Journal of Medicinal Chemistry, 2009, 52: 4650-4656.
• More, S. S.; Vince, R. Design, Synthesis and Biological Evaluation of Glutathione Peptidomimetics as Components of Antiparkinson Prodrugs. Journal of Medicinal Chemistry, 2008, 51: 4581-4588.
• 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: 1151–1158.
• 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: 2793-2797.
• More, S. S.; Vince, R. A Metabolically Stable Tight-binding Transition-state Inhibitor of Glyoxalase- I. Bioorganic and Medicinal Chemistry Letters, 2006, 16: 6039-6042.

Research Funding Grants

Retinal Changes in Alzheimer’s Disease and Cerebral Amyloid Staging Correlations in Post-Mortem Retina and Brain Samples, Validation of a Promising Early Biomarker
Duration: 01/01/19 - 12/31/19
Funding Source: Winston and Maxine Wallin Neuroscience Discovery Fund
Role: Principal Investigator (Co-I: William Robert Bell and Margaret Flanagan, Department of Lab Medicine and Pathology)

Retinal Hyperspectral Imaging: A Tool for Early Detection of Alzheimer’s Disease
Duration: 01/01/2019-12/31/2020
Funding Agency: Minnesota Partnership for Biotechnology and Medical Genomics
Role: Principal Investigator (Mayo PI: John J. Chen, Department of ophthalmology, Rochester)

Completed Research Support

Chronic Exposure to Butter Flavorants and Neurodegeneration
Duration: 01/01/2017 – 06/30/2018
Grant Source: Grant-in-Aid of Research, Artistry and Scholarship program
Role: Principal Investigator

Assessment of the efficacy of QC modulators in a cellular model of AD
Duration: 01/01/2017 – 12/31/2018
Funding Source: Contract research for Probiodrug, AG, Germany
Role: Principle Investigator

Guanabenz as a disease modifying therapeutic for Parkinson’s Disease: in vivo efficacy and chemical optimization
Duration: 01/01/2015 – 12/31/2015
Funding Source: Winston and Maxine Wallin Neuroscience Discovery Fund
Role: Co-investigator (PI, Michael Lee)

• Vince R, Singh R, More SS. Use of Tosedostat and related compounds as analgesics. U.S. Pat. Appl. Publ. (2019), US 20190282531 A1 20190919.
• More SS, Vince R. (2018) Preparation of therapeutic compounds. U.S. Pat. Appl. Publ. 2018; US 20180230105 A1 20180816.
• Vince R, More SS, Beach JM. (2017) Spectral-spatial imaging device. PCT Int. Appl. 2017, WO 2017156400 A1 20170914.
• Giacomini KM, More SS, Yee SW, Geier, E, Wilson J. (2017) Platinum anticancer agents. PCT Int. Appl. 2017, WO 2017091616 A1 20170601.
• Chen L, Ai T, More SS. (2016) Preparation of heterocyclic carboxamide derivatives useful as SIRT2 inhibitors. U.S. Pat. Appl. Publ. 2016, US 20160376238 A1 20161229.
• Vince R, More SS. (2014) Glutathione analogs and uses thereof. U.S. Pat. Appl. Publ. 2014, US 20140154192 A1 20140605. 
• 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 amine 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.