Chemical Actions and Uses Commons^™

Breaking Into Hiv-1'S Epigenetic Vault: Cure Strategies To Eliminate The Viral Reservoir, Joanna Jones, Chelsea Gunderson, Brian Wigdahl, Michael Nonnemacher

Kimmel Cancer Center Faculty Papers

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that integrates into the host cell's DNA as a provirus. Transcription from the provirus is regulated in large part by cellular proteins and epigenetic factors. These may be repressive or permissive to productive infection. The host factors that regulate this balance are therefore attractive targets for HIV-1 therapeutics. Indeed, proviral chromatin is the focus of two of the current HIV-1 cure strategies. "Shock and Kill" uses latency reversal agents to open the provirus's chromatin, promoting high levels of gene expression that induce the killing of infected cells. "Block and Lock" uses …

Ns5-Targeting Nucleoside Analogs Inhibit Dengue Virus And Other Flaviviruses, Priyanka Bhakt, Swechha Pokharel, Yue Li, Tamanna Srivastava, Jesse Miller, Mark Dittmar, Yongqing Zhu, David Nguyen, Zachary Walter, Kasirajan Ayyanathan, Matthew Tudor, Chenguang Yu, Arnab Chatterjee, Holly Ramage, David Schultz, Sara Cherry

Department of Microbiology and Immunology Faculty Papers

Dengue virus (DENV) is a mosquito-transmitted flavivirus that circulates globally as four distinct serotypes and poses a substantial threat to public health. There are an estimated ~96 million symptomatic infections yearly, including severe cases of dengue fever, underscoring the urgency of identifying effective therapeutics targeting all four serotypes. Nucleoside analogs, which mimic endogenous nucleosides to inhibit viral RNA replication, offer a promising strategy for broad-spectrum antiviral development. Here, we conducted a high-throughput screen of 1,101 nucleoside analogs against DENV serotype 2 (DENV2) in a panel of human cell models, including human epithelial cells, hepatocytes, and fibroblasts. Candidates that were active …

Hydralazine Inhibits Cysteamine Dioxygenase To Treat Preeclampsia And Senesce Glioblastoma, Kyosuke Shishikura, Jiasong Li, Yiming Chen, Nate R. Mcknight, Thomas P. Keeley, Katelyn A. Bustin, Eric W. Barr, Snehil R. Chilkamari, Mahaa Ayub, Sun Woo Kim, Zongtao Lin, Ren-Ming Hu, Kelly Hicks, Xie Wang, Donald M. O'Rourke, J. Martin Bollinger, Zev A. Binder, William H. Parsons, Kirill A. Martemyanov, Aimin Liu, Megan L. Matthews

SKMC Student Presentations and Publications

Hydralazine (HYZ), a treatment for preeclampsia and hypertensive crisis, is listed by the World Health Organization as an essential medicine. Its mode of action has remained unknown through its seven decades of clinical use. Here, we identify 2-aminoethanethiol dioxygenase (ADO), a key mediator of targeted protein degradation, as a selective HYZ target. The drug chelates ADO's metallocofactor and can alkylate one of its ligands. The resultant inactivation stabilizes regulators of G protein signaling (RGS4 and RGS5) that ADO normally marks for proteolysis, explaining the drug's vasodilatory activity and comporting with observations of diminished RGS levels in both clinical preeclampsia and …

Targeting The Bcl2 Family: Advances And Challenges In Bh3 Mimetic-Based Therapies, Nabanita Mukherjee, James Sheetz, Yiqun Shellman

Student Papers, Posters & Projects

The BCL2 family of proteins plays a pivotal role in regulating apoptosis and cellular homeostasis, making them critical therapeutic targets in cancer and other diseases characterized by pathological cell survival. BH3 mimetics, small molecules that selectively inhibit anti-apoptotic BCL2 family members, have achieved significant clinical success, particularly in hematologic malignancies. However, several challenges remain, including resistance mechanisms, toxicity (such as MCL1 inhibitor-associated cardiotoxicity), and the intricate balance between apoptotic and non-apoptotic functions. This review provides a comprehensive overview of BCL2 family biology, the development and clinical application and outcomes of BH3 mimetics, and the emerging resistance mechanism known as double-bolt …

Neovascular Pruning By Ido1 Inhibitors Can Potentiate Immunogenic Cytotoxicity Of Ischemia-Targeted Agents To Synergistically Enhance Anti-Pd-1 Responsiveness, Shih-Chun Shen, Souvik Dey, James B. Duhadaway, Erika Sutanto-Ward, Maurice T. Hampton, Serguei V. Kozlov, George C. Prendergast, Alexander J. Muller

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Strategies for deploying indoleamine 2,3-dioxygenase 1 (IDO1)-targeted therapies for use against cancer have focused on IDO1's role in promoting peripheral immune tolerance that shields tumors from effector T cells. However, preclinical investigation of both primary and metastatic tumor development in the lungs has uncovered a previously unappreciated role for IDO1 in directing a counterregulatory response to interferon (IFN)-γ that realigns the local inflammatory environment to promote tumor neovascularization. Understanding how to therapeutically leverage the ability of IDO1 inhibitors to subvert inflammatory neovascularization within the tumor microenvironment has potential ramifications for future clinical development of these compounds.

METHODS: Pulmonary metastases …

Ibuprofen, Flurbiprofen Or Naproxen Sodium Minimally Influences Musculoskeletal Adaptations To Treadmill Exercise In Rats, Brandon Roberts, Alyssa Geddis, Alexandra Ciuciu, Marinaliz Reynoso, Nikhil Mehta, Alyssa Varanoske, Alyssa Kelley, Maximus Leiss, Alexander Kolb, Julie Hughes, Marshall Naimo, Ryan Tomlinson, Jeffery Staab

Department of Orthopaedic Surgery Faculty Papers

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) may influence musculoskeletal health. The purpose of this study was to compare the effects of three different NSAIDS: naproxen sodium, ibuprofen, flurbiprofen or a placebo on musculoskeletal adaptations in rodents with or without 6 weeks of aerobic exercise.

METHODS: Nine-week-old male Wistar rats (n = 80) were randomized to either exercise (EX) or no-exercise control (CON) conditions and treated with naproxen, ibuprofen (IBU), flurbiprofen (FLU) or placebo (PLA). For exercise, rats ran 5 days per week for 6 weeks at a 5% incline on a motorized treadmill for 30 min. Three-point bending (3 PB) and …

Tryptophan Kynurenine Pathway-Based Imaging Agents For Brain Disorders And Oncology-From Bench To Bedside, Erik Stauff, Wenqi Xu, Heidi H. Kecskemethy, Sigrid A. Langhans, Vinay V. R. Kandula, Lauren W. Averill, Xuyi Yue

Jefferson Hospital Staff Papers and Presentations

Tryptophan (Trp)-based radiotracers have excellent potential for imaging many different types of brain pathology because of their involvement with both the serotonergic and kynurenine (KYN) pathways. However, radiotracers specific to the kynurenine metabolism pathway are limited. In addition, historically Trp-based radiopharmaceuticals were synthesized with the short-lived isotope carbon-11. A newer generation of Trp-based imaging agents using the longer half-lived and commercially available isotopes, such as fluorine-18 and iodine-124, are being developed. The newly developed amino acid-based tracers have been demonstrated to have favorable radiochemical and imaging characteristics in pre-clinical studies. However, many barriers still exist in the clinical translation of …

The Potential Anti-Arrhythmic Effect Of Sglt2 Inhibitors, Hong-Yi Duan, Hector Barajas-Martinez, Charles Antzelevitch, Dan Hu

Department of Medicine Faculty Papers

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) were initially recommended as oral anti-diabetic drugs to treat type 2 diabetes (T2D), by inhibiting SGLT2 in proximal tubule and reduce renal reabsorption of sodium and glucose. While many clinical trials demonstrated the tremendous potential of SGLT2i for cardiovascular diseases. 2022 AHA/ACC/HFSA guideline first emphasized that SGLT2i were the only drug class that can cover the entire management of heart failure (HF) from prevention to treatment. Subsequently, the antiarrhythmic properties of SGLT2i have also attracted attention. Although there are currently no prospective studies specifically on the anti-arrhythmic effects of SGLT2i. We provide clues from …