current research focus in umesiri lab

Current research focus in the Umesiri lab is development of novel poly-N-substituted glycines (peptoids), as potential nueroprotective and antimicrobial agents.

Developing New Peptoids as Neuroprotective Agents against Ischemic Stroke.

Project Goal: The long-term goal of the project is the synthesis and biological evaluation of a set of new peptoids with neuroprotective properties against ischemic stroke using naked mole rats.

Background: According to recent data published by the American Heart Association and the American Stroke Alliance, stroke is the fifth leading cause of death, and the leading cause of long-term disability in the United States (1). Each year, approximately 795,000 stroke cases are reported in the United States, resulting in 133,000 deaths annually.1 Furthermore, 87% of all strokes reported are ischemic stroke.1 Ischemic stroke occurs when a clot blocks a blood vessel, cutting off blood flow, including oxygen and nutrients, to a portion of the brain. When this happens, neuronal brain cells are damaged, unless blood flow and nutrient supply are immediately restored to the brain. The revascularization of blocked cerebral arteries using tissue plasmogen activator (Alteplase, r-tPA), the only FDA-approved treatment for ischemic stroke, has proven effective for some patients, but only if the patient is able to receive the treatment within 4.5h time frame after the onset of a stroke (1-2). Hence, there is a continuing, if not urgent, need to develop new neuroprotective agents against ischemic stroke. New Peptoids as Potential Neuroprotective Agents for Ischemic Stroke: Interestingly, a few animal models, such as the naked mole rat, exhibit unique adaptation to acute hypoxia, and have become a thriving area of study for clues on adaptive mechanisms against hypoxia/ischemia which may be translated to clinical application for development of neuroprotective agents against ischemic stroke (3-4). Therefore, the current study has the objective to synthesize a set of new peptoids and screen for neuroprotective effects in hypoxic/ischemic conditions in naked mole rats. Long term, the study aims to determine whether evidence of tolerance to oxygen nutrient deprivation exists in the chronic cultures of the naked mole rat’s hippocampal slices administered with different doses of new synthetics. We plan to use oxygen nutrient deprivation (OND), an in vitro model of hypoxia tolerance, to determine neuronal survival in the hippocampal slices of mole rats(3-5). Study is in two phases: first stage is the synthesis of the new peptoids, samples of which are represented in Figure 1; while second stage is the biological evaluation of new synthetics in animal models.

Peptoids as antimicrobial agents

Peptides are small chains of linked amino acids, with different functions in the body. Studies have shown that peptides display antimicrobial activity. Peptoids, close peptides mimetics, have also shown promising signs of antimicrobial activity, with the added benefit of longer lasting effects, due to their resistant protease degradation in vivo (6). Because of the unique potential of peptoids, the Umesiri laboratory is focused on the search for novel peptoids with antimicrobial activity against a variety of common microbial pathogens. One significant pathogen for which new drug development is urgently needed is Mycobacterium tuberculosis (MTB). Antigen 85 is an enzymatic complex with a critical role in synthesis and maintenance of the bacterial cell wall of MTB (7). Antigen 85 is a promising target for drug development because of its extracellular location, its presence in humans, and its affinity for hydrophobic compounds (8). Microbial susceptibility tests are done using Kirby-Bauer disk assay against Mycobacterium smegmatis (M. smegmatis), Staphylococcus aureus ( S. aureus), and E. coli. Minimum inhibitory concentration assays are based on risazurin (alamar blue) cell viability assay.

References

1. Heart Disease and Stroke Statistics 2017 At-a-Glance. American Heart Association, and American Stroke Association. https://www.heart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm_491265.pdf. Accessed March 10, 2017.

2. R.S. Pandya, L. Mao, H. Zhou, S. Zhou, J. Zeng, A.J. Popp, X. Wang. Central Nervous System Agents for Ischemic Stroke: Neuroprotection Mechanisms; Cent Nerv Syst Agents Med Chem. 2011 June 1; 11(2): 81–97.)

3. T.I. Nathaniel, A. Saras, F.E. Umesiri, F. Olajuyigbe. Tolerance to Oxygen Nutrient Deprivation in the Hippocampal Slices of the Naked Mole Rats. J. Integr. Neurosci. 2009; 8, 123-136.

4. T.I. Nathaniel, F.E. Umesiri, G. Reifler, K. Haley, L. Dziopa, J. Glukhoy, R. Dani. “Physiological Neuroprotective Mechanisms in Natural Genetic Systems: Therapeutic Clues for Hypoxia-Induced Brain Injuries” In Brain Injury – Pathogenesis, Monitoring, Recovery and Management, A. Agrawal (ed.), InTech, 2012.

5. N.L.B. Pohl, K. Kirshenbaum, B. Yoo, N. Schulz, C.J. Zea, J.M. Streff, K.L. Schwarz. Student-Driven Design of Peptide Mimetics: Microwave-Assisted Synthesis of Peptoid Oligomers. J. Chem. Educ. 2011, 88, 999–1001.

6. Czyzewski AM, Jenssen H, Fjell CD, Waldbrook M, Chongsiriwatana NP, Yuen E, et al. (2016) In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents. PLoS ONE 11 (2): e0135961. doi:10.1371/journal.pone.0135961

7. Boucau, J. Sanki, A.K. Voss, B.V. Sucheck, S.J. Ronning, D.R. Anal. Biochem. 2009. 385 120-127.

8. Umesiri, F. E. Funk, J. Lick, A. Fricke, C. Nathaniel, T.I. Med. Chem. 2015. 5:437-441. doi: 10.4172/2161-0444.100029.