Auburn Research Day 2022

Rishi M. Nadar 1 ; Rachel Parise 1 ; Sindhu Ramesh 1 ; Jack Deruiter 1 ; Muralikrishnan Dhanasekaran 1 ; Manoj Govindarajulu 1 ; Timothy Moore 1 1 Department of Drug Discovery and Development, Auburn University Harrison School of Pharmacy, Walker Building Cl i n i ca l Resea rch | Gr adua te/Undergr adua te St udent Impact of COVID-19 Therapy on Hyperglycemic Patients: A Systematic Clinical Review for Effective Global Healthcare 69

Background: Infection, stress, illicit drugs, improper dietary intake, noncompliance to anti-diabetic medications, and physical inactivity are considered risk factors for hyperglycemia. Hyperglycemia is deemed as an independent risk factor for various long-term or emergency complications. The American Diabetes Association (ADA) reported an increased risk of severe complications from SARS-CoV-2 (COVID-19) infection in patients with diabetes mellitus (type 1 or type 2). Viral infections can evoke a “cytokine storm”, leading to acute and/or chronic inflammation. In diabetic mellitus, high blood glucose levels contribute to inflammatory pathology and prevalence of severe complications, with elevated diabetic/hyperglycemic morbidity and mortality. The Centers for Disease Prevention and Control (CDC) has issued a statement that adults with type 1 or type 2 diabetes mellitus can be at an increased risk for severe illness from COVID-19, including hospitalization, intensive care, ventilation, or death. Goals and Aims: The goal of this study was to analyze the effect of COVID-19 drugs and biologicals on hyperglycemia. The hypothesis is that effective COVID-19 treatment improves hyperglycemia through eradication of the infection, but these treatments may also alter BG levels by other mechanisms. Materials and Methods: A literature search with key terms, such as “COVID-19 drugs and hyperglycemia” and “COVID-19 vaccines and hyperglycemia”, was conducted using PubMed through

September 2021. The CDC data were referenced for the current COVID-19 profile and statistics. The NIH COVID-19 guidelines were referenced for updated treatment recommendations. Micromedex and

UpToDate were used for drug and disease information. Results: Current results suggested that corticosteroids

(dexamethasone), remdesivir, and antivirals (lopinavir, and ritonavir) all have the potential to significantly raise blood glucose levels putting patients at elevated risk for severe complications. On the contrary, hydroxychloroquine is associated with hypoglycemia, and tocilizumab (IL-6 inhibitor) decreases inflammation which is associated with improving glucose levels. Other anti-cytokine bioactive molecules, including anakinra (anti-IL-1 receptor) and TNF-alpha inhibitors, are correlated with lower blood glucose in patients with and without diabetes mellitus. Ivermectin, used for mild COVID-19 disease, possesses the potential for lowering blood glucose, as well. Comastat mesylate, undergoing a current clinical trial, is also associated with decreasing blood glucose. Reports from diabetic patients noted higher blood sugar levels at 1-7 days post-vaccination. Covishield, Pfizer BioNTech, and Moderna have all been associated with hyperglycemia after the first dose. Conclusion: Individualized / personalized patient care is required for hyperglycemic patients with COVID-19 infection. Improper drug therapy aggravates hyperglycemic conditions and other comorbid conditions, leading to increased morbidity and mortality.

Fajar Setyo Wibowo 1 ; Ian Steinke 1 ; Sieun Yoo 1 ; Forrest Smith 1 ; Juming Zhong 2 ; Rajesh H. Amin 1 1 Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University; 2 Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University B i omed i ca l Resea rch | Gr adua te/Undergr adua te St udent Design and Development of Novel LXR β -Selective Agonist for Alzheimer’s Disease 70

Liver X receptors (LXRs) are nuclear receptors that serve as lipid- responsive transcription factors and exist as two isoforms in the body, LXR α and LXR β . Further, LXRs are mainly available in the liver and brain. LXR α is highly abundantly expressed in the liver, when compared to LXR β . Conversely, in the brain, LXR β is five times more abundant in expression than LXR α . Recently, LXR agonist are famous for the treatment of atherosclerosis because they are involved in the reverse cholesterol transport (RCT) from macrophages by increasing expression of ApoE and cholesterol efflux transporters ABCA1 and ABCG1. However, current LXR full agonist (GW3965 and T0901317) have been shown to increase liver and plasma triglycerides and Low- Density Lipoprotein (LDL). Recent reports have indicated that LXR is highly significant in the brain for lipidation of ApoE and formation of the ApoE-A β complex, which results in the clearance of A β in the brain. Targeting LXR β is beneficial in the brain, as it will increase the clearance of A β . Our goal

is to design and develop novel LXR β agonists that target the brain without inducing liver steatosis. To validate LXR activity, we tested LXR full agonist (GW3965 and T0901317) using lipid accumulation assay in HEPG2 cells. GW3965 and T0901317 displays increase of lipid accumulation in HEPG2 cells when compared to control. Our lead compound, AU-418LA, was designed computationally with an emphasis on ADME using Schrodinger and GastroPlus modeling software. Our in-silico design was formulated around diminishing interactions with the Arg-305 (LXR α ) and Arg-319 (LXR β ). A residue responsible for full activation that leads to lipid accumulation. Based on the docking score, AU-418LA preferably binds to LXR β (-10.632) than LXR α (-7.644), compared to full agonist GW3965 with docking score of -15.424 (LXR β ) and -14.588 (LXR α ). Our future aims are to synthesis the AU-418LA and series of LXR β -selective agonists and test them using reporter activity and lipid accumulation assays, also provide crystal structure of AU-418LA bound to the LXR receptor.

41 2022 Via Research Recognit ion Day