Medicinal and Pharmaceutical Chemistry Commons^™

Tumor Targeting With Peptide-Drug Conjugates: Showcasing Key Progress And Hurdles, Keykavous Parang, Thuy Do, Clare Dinh, Dorna Davanidavari, Max Foroughi, Troy Khong, Mahsa Moazen, Amir Nasrolahi Shirazi

Pharmacy Faculty Articles and Research

Peptide-drug conjugates (PDCs) are modular, targeted therapeutics composed of a homing peptide linked to a cytotoxic or modulating drug payload via a cleavable/non-cleavable linker. PDCs utilize peptide targeting to enhance the delivery of potent drugs to tumors, providing advantages such as superior tissue penetration, reduced immunogenicity, and simpler manufacture compared to antibody-drug conjugates (ADCs). A comparison of PDCs versus ADCs highlights that PDCs’ small size (~1-3 kDa) enables deeper tumor penetration and faster clearance, whereas ADCs (~150 kDa) benefit from prolonged circulation but suffer from limited tissue diffusion. This review surveys recent advances in PDC design and application. We discuss …

Protein Allostery Probed By Ligands Across Sites, Virgil A. Woods

Dissertations, Theses, and Capstone Projects

Allostery is a pervasive regulatory principle throughout biology, yet the structural pathways by which distal inputs alter active‑site chemistry within protein structures remain incompletely defined and exploited. This dissertation uses protein tyrosine phosphatase 1B (PTP1B) as a tractable model to map those pathways with complementary experimental and computational tools. I integrate high‑resolution hydrogen-deuterium exchange mass spectrometry (HDX-MS), room-temperature crystallography, NMR, steady-state kinetics, crystallographic pseudo-ensembles, and machine-learning-guided ligand discovery. The working premise is that regulation reflects redistribution within a conformational ensemble rather than a binary switch. That orthogonal perturbations by small molecules, mutations, and protein partners can be used to both …

Dual Tyk2/Jak1 Inhibition By Brepocitinib Reprograms Synoviocyte Pathobiology: Mechanistic Insights Into Targeted Therapy For Rheumatoid Arthritis, Umar Saeed, Zahra Zahid Piracha, Andromeda M. Nauli, Surya M. Nauli

Pharmacy Faculty Articles and Research

Background:

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial hyperplasia, persistent inflammation, and joint destruction. Targeted inhibition of intracellular signaling pathways, such as JAK-STAT, has improved RA treatment outcomes, though safety and selectivity remain as concerns. Brepocitinib, a dual TYK2/JAK1 inhibitor, has shown clinical efficacy in the management of autoimmune diseases, yet its mechanistic impact on synoviocytes remains underexplored.

Objectives:

To investigate the molecular and functional effects of brepocitinib on MH7A and RA-FLS synoviocytes, a key effector cell type in RA pathogenesis.

Methods:

MH7A and RA-FLS cells were treated with brepocitinib (0.5 µM, 1 µM, and 5 …

New Inhibitors Of Neuronal Nitric Oxide Synthase For The Treatment Of Melanoma, Amardeep Awasthi, Anika Patel, Huiying Li, Koon Mook Kang, Christine D. Hardy, Anas Ansari, Raghad Nowar, Hasan Alhaddad, Md. Emtiaz Hasan, Sun Yang, Thomas L. Poulos, Richard B. Silverman

Pharmacy Faculty Articles and Research

In 2024, an estimated 100,640 new cases of invasive melanoma were diagnosed in the U.S., with 9290 deaths. Our previous studies revealed that neuronal nitric oxide synthase (nNOS) derived nitric oxide plays a critical role in melanoma progression, making nNOS inhibition a promising strategy. High structural similarity among NOS isoforms requires careful design of nNOS inhibitors to avoid off-target effects. Our previous lead, HH044, demonstrated potent antimelanoma activity but exhibited only moderate nNOS selectivity. Here, we utilized a structure-based approach to design nNOS inhibitors that promote interactions with human nNOS-specific residue His342. Compound 9 exhibited inhibition of both human ( …

Molecular Survival Strategies Against Kidney Filtration: Implications For Therapeutic Protein Engineering, William Heaps, Anna Elise Packard, Kristina M. Mccammon, Tyler P. Green, Joseph P. Talley, Bradley C. Bundy, Dennis Della Corte

Faculty Publications

The glomerular filtration barrier poses a significant challenge for circulating proteins, with molecules below ~60–70 kDa facing rapid renal clearance. Endogenous proteins have evolved sophisticated evasion mechanisms including oligomerization, carrier binding, electrostatic repulsion, and FcRn-mediated recycling. Understanding these natural strategies provides blueprints for engineering therapeutic proteins with improved pharmacokinetics. This review examines how endogenous proteins resist filtration, evaluates their application in protein engineering, and discusses clinical translation including established technologies (PEGylation, Fc-fusion) and emerging strategies (albumin-binding domains, glycoengineering). We address critical challenges of balancing half-life extension with tissue penetration, biological activity, and immunogenicity—essential considerations for the rational design of next-generation …

Direct Effects Of Capsaicin On Voltage-Dependent Calcium Channels Of Mammalian Skeletal Muscle, Dmytro Isaev, Tatiana Prytkova, Badarunnisa Mohamed, Mohamed Omar Mahgoub, Keun-Hang Susan Yang, Murat Oz

Pharmacy Faculty Articles and Research

Capsaicin, a naturally occurring polyphenol, is known to affect energy expenditure and muscle fatigue and modulate contractions in skeletal muscle. The L-type Ca²⁺ channels are known to be an important ion channel involved in the various muscle functions and the effect of capsaicin on the skeletal L-type Ca²⁺ channels is currently unknown. In this study, the effects of capsaicin and capsaicin analogs on depolarization-induced Ca²⁺ effluxes through L-type Ca²⁺ channels in transverse tubule membranes from rabbit skeletal muscle and L-type Ca²⁺ currents recorded using the whole-cell patch clamp technique in rat myotubes were examined. Capsaicin, …

Fda Policy Shift On Clinical Efficacy Study Requirements For Monoclonal Antibody Biosimilars, Rileigh Rahrig, Madilyn Paphanchith, Allie Honigford, Daniella Egbujor, Haley Brown, Jenny Magana Figueroa, Connor Dains, Brenna Hissong, Kyle W. Parker

Pharmacy and Wellness Review

Biologic products are widely used in the treatment of various disease states, including rheumatoid arthritis, inflammatory bowel disease, cancers, and genetic diseases. These products are derived from proteins and genes produced by living organisms and are subsequently used to treat specific disease states. Due to the complexity of biological products, the costs of research and production are high. Currently, the United States approval pathway requires extensive testing for biologics to be designated as biosimilars, meaning there are no clinically meaningful differences in safety or purity of their active components. These required tests can be redundant, as biosimilars are developed using …

Impact Of Apitegromab On Motor Function In Spinal Muscular Atrophy, Jordyn Linfield, Ashley Jacob, Haylee Whyde, Owen Fox, Kaitlyn Bowden, Connor Dains, Brenna Hissong, Manoranjan D'Souza

Pharmacy and Wellness Review

Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder characterized by the progressive loss of alpha motor neurons in the anterior horn of the spinal cord, leading to muscle weakness, atrophy, and impaired motor function.¹ SMA remains an extensive and difficult-to-treat condition, with only three disease-modifying therapies currently available to patients. A new investigational agent with a unique mechanism of action, apitegromab (SRK-015), has shown promising results in recent clinical trials. The safety and efficacy of apitegromab in patients with SMA have been explored in several clinical trials, with the TOPAZ and SAPPHIRE studies being the most notable. This …

Fda Approval Of The Eversense 365 Continuous Glucose Monitoring System: A New Era In Long-Term Glucose Monitoring, Kiley Devoll, Alexander Defranco, Kennedy Kosikowski, Anna Spalvieri, Macy Davis, Connor Dains, Brenna Hissong, Emily Eddy

Pharmacy and Wellness Review

Eversense 365 is an implantable continuous glucose monitoring (CGM) system designed to provide accurate glucose measurements for up to 365 days. Current clinical guidelines recommend CGM use for patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), with evidence demonstrating benefit in patients with T2DM regardless of concurrent insulin use. Healthcare providers play a key role in patient education and are well-positioned to support the adoption of long-term CGM technologies, including Eversense 365. The safety and efficacy of the 365-day CGM have been evaluated across a series of clinical trials, which demonstrate clinically meaningful improvements in …

Structural Basis For The Subtype-Selectivity Of KCa2.2 Channel Activators, Young-Woo Nam, Alena Ramanishka, Yang Xu, Rose Marie Haynes Yasuda, Joshua A. Nasburg, Dohyun Im, Meng Cui, K. George Chandy, Heike Wulff, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance (K_Ca2.2) and intermediate-conductance (K_Ca3.1) Ca²⁺-activated K⁺ channels are gated by a Ca²⁺-calmodulin dependent mechanism. NS309 potentiates the activity of both K_Ca2.2 and K_Ca3.1, while rimtuzalcap selectively activates K_Ca2.2. Rimtuzalcap has been used in clinical trials for the treatment of spinocerebellar ataxia and essential tremor. We report cryo-electron microscopy structures of NS309-bound K_Ca2.2 and K_Ca3.1, in addition to structures of rimtuzalcap-bound K_Ca2.2 and mutant K_Ca3.1_R355K. The different conformations of calmodulin and the cytoplasmic HC helices in the …

Evaluation Of Peptides And Peptide–Doxorubicin Conjugates Designed And Synthesized For Targeting Triple-Negative Breast Cancer Via Cell-Surface Receptors, Shih-Jing (Jane) Yao

Pharmaceutical Sciences (PhD) Dissertations

A significant problem faced in oncology is the lack of chemotherapeutic agents that are tumor site-specific, resulting in reduced therapeutic efficacy and unintended infliction of harm to surrounding healthy tissues and cells that often lead to serious side effects. Current strategies being explored to circumvent this issue aim to refine delivery of  chemotherapeutic agents specifically to tumor sites, which may be achieved via conjugation of these agents to biomarker-specific ligands. This forms the foundation of ligand-targeted drug delivery. Among different breast cancers, treatment of the triple-negative breast cancer (TNBC) subtype has been particularly challenging, largely due to the absence of …

Evaluation Of The Physical Properties And In Vitro Safety Of Chitosan-Quercus Infectoria Topical Gel, Rani Naga Rakshitha Tillapudi

Theses, Dissertations and Capstones

Due to ongoing inflammation, inadequate blood flow, oxidative stress, and reduced tissue regeneration, chronic diabetic wounds heal slowly, which is a serious health concern. It is important to examine novel strategies that tackle these issues because conventional treatments frequently fail. Therefore, this study examined the physical properties and biocompatibility of a novel topical gel formulated with chitosan and Quercus infectoria gall extract.

Over 28 days, pH, spreadability, texture, homogeneity, color, and drug concentration were assessed. UV-visible spectrophotometry and FTIR analysis were used to establish chemical stability. The MTT assay was used to test its safety in human dermal fibroblast adult …

Proteome-Based Identification And Validation Of Nxpe3 In Childhood Acute Lymphoblastic Leukaemia, Najia Tabassum, Yamna Khurshid, Basir Syed, Aftab Ahmad, Sadia Muhammad, Rehan Imad, Talat Mirza

Pharmacy Faculty Articles and Research

Background: Childhood acute lymphoblastic leukaemia (cALL) tends to metastasize to central nervous system. Treatment with antileukemic agents against CNS leukaemia is an essential component for cure in ALL. Hence, it is essential to identify biomarkers for CNS infiltration. Proteomics, supported by mass spectrometry, is the platform for exploring biomarkers in various biological samples, contributing to translational research. Objectives: This study aimed to identify the plasma proteome profile of children across different risk groups of cALL. Neurexophilin and PC-esterase family, member 3 (NXPE3), was validated. The protein-protein interactions (PPI) of NXPE3 were evaluated with bioinformatics analyses. Methods: Plasma …

Nanocomposite Mediated Delivery Of 5-Fluorouracil Using Silver Nanoparticles To Promote Wound Healing, Kamal Nath Kasi

Theses, Dissertations and Capstones

Chronic wounds, particularly in diabetic patients, remain a significant clinical challenge due to the complex interaction of persistent infection, chronic inflammation, and impaired cellular regeneration. Conventional drug therapies often fail to achieve effective treatment due to rapid drug degradation, poor targeting, and localized toxicity. This study explores a nanotechnology-based approach by developing and evaluating 5-FU loaded AgNP (AgNP–5FU) as a controlled drug delivery system. AgNP (AgNP) were synthesized and characterized using scanning electron microscopy (SEM), energy dispersive X-ray (EDX) analysis, particle size, and zeta potential analysis, while Fourier Transform Infrared Spectroscopy (FTIR) analysis suggested possible interaction between 5-FU and the …

Development And In Vitro Characterization Of 5-Fluorouracil–Loaded Plga Nanoparticles For Controlled Drug Delivery, Kavya Yandapalli

Theses, Dissertations and Capstones

Non-Alcoholic Fatty Liver Disease (NAFLD) is a progressive metabolic disorder characterized by excessive lipid accumulation in hepatocytes and chronic inflammation. Nanoparticle-based drug delivery systems offer a promising strategy to enhance therapeutic efficacy while minimizing systemic toxicity. The objective of this study is to formulate and characterize 5-FU–loaded PLGA nanoparticles and evaluate their in vitro performance. 5-FU–loaded PLGA nanoparticles were prepared using the double emulsion solvent evaporation method. The nanoparticles were characterized by particle size, polydispersity index, zeta potential and SEM. Drug encapsulation efficiency, loading capacity and in vitro drug release studies were conducted. The formulated nanoparticles exhibited sizes within the …

Development Of Tunable Rose Bengal Based-Nanogumbos As Potential Selective Chemotherapeutic Agents, William J.A. Russell

Honors College Theses

As cancer remains one of the greatest threats to the global population, the development of chemotherapeutic agents that are selective and tunable is of critical importance. Herein, a series of Rose Bengal (RB)-based GUMBOS, a group of uniform materials based on organic salts, were synthesized via counterion exchange between [Na]₂[RB] and three organic cations: tetrabutylphosphonium bromide [TBP][Br], tetraphenylphosphonium chloride [TPP][Cl], and 1-dodecyl-3-methylimidazolium chloride [C₁₂MIm][Cl]. The resulting GUMBOS were characterized through FT-IR, ESI-MS, NMR, and UV-Vis Spectroscopy. Partition coefficient studies indicated all GUMBOS exhibited hydrophobic physiochemical characteristics. These hydrophobic RB-based GUMBOS …

Formulation Development Of Topical Inserts Containing Doxycycline And Doxycycline Combined With Tenofovir Alafenamide And Elvitegravir For The Prevention Of Sexually Transmitted Infections, Vivek Agrahari, M. Melissa Peet, Jasmin Monpara, Rijo John, Sriramakamal Jonnalagadda, Pardeep K. Gupta, Meredith R. Clark, Gustavo F. Doncel

CONRAD Publications

Despite advances in oral and injectable HIV prevention options and oral prophylaxis for sexually transmitted infections (STIs) of bacterial origin, there remains a critical need for effective on-demand topical (vaginal and rectal) products for pre- and post-exposure prophylaxis (PrEP and PEP). To fill this gap, we have developed single and first-in-kind multi-active topical inserts for bacterial STIs and HIV/STIs prevention. We have formulated two different inserts, one containing doxycycline (DOX) at 10, 50, and 100 mg doses for bacterial STI prevention, and a multipurpose prevention product (TED insert) that combines DOX (10 mg) with the antiretrovirals tenofovir alafenamide (TAF; 20 …

Developing Curcumin Analogues For Treating Breast Cancer, Tulasi Laxmi Nutalapati

Theses, Dissertations and Capstones

Breast cancer is still one of the most common types of cancer and one of the most common causes of cancer-related deaths in women around the world. Despite significant advances in early detection and treatment strategies, drug resistance, systemic toxicity, and poor outcomes in aggressive subtypes continue to limit the overall effectiveness of cancer therapy. Natural compounds have become promising anticancer agents because they can target many different things and are not very toxic. Curcumin has shown promise as an anticancer drug, but it cannot be used in the clinic because it does not absorb well, breaks down quickly, and …

Metabolomics Driven Discovery Of Bioactive Natural Products Leads From Marine And Terrestrial Sources For The Development Of Analgesics, Sahar Mofidi Tabatabaei

University of Kentucky Doctoral Dissertations

Natural products remain a rich source of structurally diverse bioactive compounds for drug discovery, particularly for pain therapeutics. However, the chemical complexity of natural product extracts presents significant challenges for the efficient identification and prioritization of bioactive metabolites. This dissertation integrates untargeted LC-MS/MS-based metabolomics, molecular networking, classical natural products chemistry, and neurobiological assays to accelerate the discovery of analgesic lead compounds targeting the emerging pain-associated receptor σ₂R/TMEM97.

An untargeted metabolomics workflow was developed to systematically profile complex biological extracts and guide bioactive compound isolation. High-resolution LC-MS/MS data were analyzed using molecular networking (GNPS/GNPS2) to visualize chemical space, dereplicate known metabolites, …

Investigating The Role Of Traditional Chinese Herbal Medicine For Cancer Symptom Management In Older Adults: A Rapid Review, Isabelle C. Karshner

Honors Undergraduate Theses

Background: Patients with cancer often experience symptoms related to disease, complications, and treatment. One potential method of alleviating these symptoms is traditional Chinese herbal medications (TCHM). This rapid review explores the role of traditional Chinese herbal medications in treating cancer-related symptoms in older adults.

Purpose: The purpose of this rapid review is to gain and provide a better understanding of the effects of TCHM on cancer-symptom management in the older adult population. This review explores the association between TCHM and effects on cancer symptoms in older adults, including interactions, toxicity, and signs/symptoms of TCHM use that may be useful information …