Current Fellow Spotlights: Research at the Chemistry-Biology Interface

Current CBI Fellows:

Kyle Davis

Orthoflaviviruses remain one of the arboviruses of greatest public health concern, with more than 4 billion people currently living in regions at risk for dengue virus (DENV) and other flaviviral infections. In 2025, dengue infections reached exceptionally high levels with over 5 million confirmed infections and nearly 2,000 deaths worldwide. In addition to mosquito-borne flaviviruses, tick-borne flaviviruses also represent a significant public health threat. Tick-borne encephalitis virus (TBEV) is endemic across both Europe and Asia, causing an estimated 12,000 clinical cases worldwide each year. Filoviruses, such as Ebola virus (EBOV), are one of the most lethal viruses with fatality rates ranging from 25% to over 90%. Despite the recognition of emerging and re-emerging viral threats from across multiple viral families, and the availability of vaccines for several of these viral pathogens, approved antiviral therapies remain severely limited or unavailable for many of them, highlighting the urgent need for improved antiviral preparedness and the development of broad-spectrum antiviral therapeutics. Nucleoside analogues are a cornerstone of antiviral therapy due to their ability to mimic natural nucleos(t)ides and inhibit viral replication. Fleximer nucleoside analogues contain a single carbon-carbon bond between the imidazole and pyrimidine moieties of the purine ring that introduces flexibility into the nucleobase. This adaptability gives fleximers the potential for increased potency, broad-spectrum antiviral activity, and resistance against point mutations. Another promising strategy involves modification of the 4’-position of the sugar moiety with the addition of fluoro, azido, or ethynyl functional groups. These modifications stabilize the sugar pucker into a North-type conformation, which is favored by viral polymerases, enhancing potency while reducing off-target effects. My research combines the fleximer technology with 4’- modifications, resulting in a series of novel 4’-modified fleximer nucleoside analogues. Preliminary data shows that several of these compounds are potent, broad-spectrum inhibitors across multiple viral families with low single-digit micromolar EC50 values against DENV, WNV, ZIKV, TBEV, EBOV, SARS-CoV-2, and others.

Notable publications and presentations:

  1. Davis, K. A.; Slack, R.; Foulkes, T. R.; Frčková, T.; Tomková, L.; Smith, J. L.; Amare, M.; Pipher, G.D.; Halfmann, P.; Sarafianos, S.; Hirsch, A. J.; Seley-Radtke, K. L. Discovery of 4’-Azido Fleximer Nucleoside Analogues with Broad-Spectrum Antiviral Activity Against DENV, EBOV, and Other Viruses. ChemMedChem. (Submitted).
  2. Davis, K. A.; Smith, J. K.; Smith, J. L.; Amare, M.; Diefenbacher, M. V.; Halfmann, P.; Sheahan, T. P.; Hirsch, A. J.; Seley-Radtke, K. L. Exploration of 4′-fluoro fleximer nucleoside analogues as potential broad-spectrum antiviral agents. Bioorganic & Medicinal Chemistry 2025, 128.
  3. Martin-Ghoteimi, C.†; Davis, K. A.†; Ghoteimi, R.; Amare, M.; Diefenbacher, M. V.; Kutz, C.; Smith, J. L.; Stevens, L. J.; Tchesnokov, E.; Walker, S. M.; et al. Novel tricycle expanded purine nucleosides with pan-viral activity. Bioorganic & Medicinal Chemistry 2025, 130. (†Co-first author).

Sean O’Sullivan

Electronic cigarette (e-cigarette) usage has risen dramatically over the past few decades, with more than 2.5 million adolescents using them in 2022. Data suggests that e-cigarette usage is linked to increased depression, anxiety, and worsening cognitive capabilities. E-cigarette vapors contain a mixture of harmful chemicals including propylene glycol, formaldehyde, glycerin, flavorants, nicotine and heavy metals. The strong sensation of pleasure from e-cigarettes is derived from  flavors in the vapor, which are detected by gustatory and olfactory neurons in the tongue and nose, respectively. E-cigarette exposure on the main olfactory epithelium (MOE) is of particular concern because of the potential to transfer harmful chemicals into the olfactory bulb (OB), whose connections to the MOE traverse without the blood-brain barrier. In the case of e-cigarette derived heavy metals which are produced from repeated use of the heating coils, this allows a potential pathway for metals to traffick their way through olfactory sensory neurons (OSNs) into the MOE, OB, and higher order regions of the brain. The olfactory system and connected regions like the hippocampus, amygdala, and anterior olfactory cortex are some of the first brain regions to show signs of neurodegeneration, and loss of smell is a highly reported prodromal symptom of mental illness and neurodegenerative diseases. My thesis work aims to discover the mechanism of e-cigarette derived heavy metal uptake through the MOE, and to identify the downstream consequences of exposure on cellular/tissue functions and various olfactory and cognitive-guided behaviors using mice as a model system.

Notable publications and presentations:

  1. O’Sullivan, S.M; Lin, W. The Impacts of E-Cigarettes on Mitochondrial Health in Olfactory Epithelial Cells. Greater Baltimore Society for Neuroscience Annual Meeting (September 2022). (Poster)
  2. O’Sullivan, S.M; Lin, W. Effects of Heavy Metals on Mitochondria and Intracellular Calcium in Mouse Olfactory Neurons. UMBC Graduate Association of Biological Sciences Symposium (March
    2023) at the 14th Frontiers in Chemistry and Biology Symposium (May 2023). (Poster)

Bethel Beyene

The Enterovirus genus comprises positive-sense (+) RNA viruses with a significant impact on global health. With over 300 different serotypes and genotypes, major human-infecting enteroviruses include coxsackievirus (CV), poliovirus (PV), and rhinovirus (RV). Although they cause a wide range of symptoms, globally approved vaccines are available only for poliovirus, and no antivirals against any enterovirus exist. Similarities in their genome organization and viral life cycle could present potential universal targets, but mechanistic details on the genome structure-function relationship remain elusive. An enteroviral genome contains a single open reading frame flanked by 5′ and 3′ UTRs, with modular domains essential for viral genome replication and translation. The first domain of the 5′ UTR—notated as the cloverleaf (5′ CL) from secondary structure predictions—is crucial for replicating (+) RNA into its template, negative (-) RNA. Work from Bethel’s laboratory has published high-resolution crystal structures of the CVB3, RVB14, and RVC15 5′ CLs, revealing that they form a highly conserved H-type four-way junction that recruits viral RNA-dependent RNA polymerase (RdRp) and the host poly(C)-binding protein (PCBP). Since the (+) RNA contains a 5′ CL, the complementary (-) sense RNA is expected to share a similar structure at the 3′ end, proposed to facilitate the synthesis of (+) RNA by assembling viral and host proteins in a manner analogous to the 5′ CL. To date, no high-resolution structures of the 3′ CL are available. Using a Fab-assisted X-ray crystallographic approach, along with biochemical assays and probing, Bethel aims to study the enteroviral 3′ CLs by determining their high-resolution crystal structure and examining interactions with the replication-related proteins: viral 2C, host hnRNP C, and the viral RdRp. Bethel is currently conducting crystallization screening to identify optimal conditions for crystal growth that will yield diffraction-quality crystals of the 3′ CL-Fab complexes. The investigation of 3′ CLs will broaden the potential targets for drug development against enteroviruses.

Notable publications and presentations:

  1. Lu, G. †, Beyene, B. G.†, Camacho, J. M., & Koirala, D. Roles of RNA Structures in the Genome Translation of (+) Sense RNA Viruses. Viruses 17, 1404 (2025). † Co- first author.
  2. Grossman, B. D., Beyene, B. G., Tekle, B., Sakowicz, W., Ji, X., Camacho, J. M., Vaishnav, N., Ahmed, A., Bhandari, N., Desai, K., Hardy, J., Hollman, N. M., Marchant, J., & Summers, M. F., Optimized Preparation of Segmentally Labeled RNAs for NMR Structure Determination. J. Mol. Biol. 437, 169073 (2025).
  3. Beyene, B. G., Abdelghani, R., Ojha, M., & Koirala, D., “Investigating the structural characteristics of (–) strand cloverleaf RNA and its roles in enteroviral (+) strand genome synthesis”, 9th UMBC Chemistry/Biochemistry Graduate Research Day (March 13, 2026), UMBC Annual Research Symposium (April 2026). (Poster)
  4. Beyene, B. G., Abdelghani, R., Ojha, M., & Koirala, D., “Investigating the structural characteristics of (–) strand cloverleaf RNA and its roles in enteroviral (+) strand genome synthesis”, 2026 ASBMB Annual Meeting, March, 2026. (Poster)

Vanshika Patel

Asthma affects over 358 million people globally, with the World Health Organization estimating 250,000 premature deaths annually. In chronic asthmatic patients, airway remodeling is a major hallmark that is challenging to reverse and can be irreversible. Current therapies often fail to reverse this remodeling, creating a need for novel approaches to inhibit airway remodeling. A novel target includes AP-1, a transcription factor complex located downstream of the ERK1/2 pathway. AP-1 plays a central role in regulating genes involved in inflammation and cell proliferation. In parallel, retinoic acid, a key metabolite of vitamin A, inhibits AP-1 activity and is notably reduced in asthmatic airway tissues. My research investigates how an ERK1/2 modulator and RAR agonists modulate AP-1 signaling to inhibit airway remodeling, using asthma-relevant cell models and mass spectrometry-based proteomics to study proteins and pathways affected in response to the chemical perturbations at the cellular and molecular level. Current studies also focus on investigating the mechanism of retinoid regulation of AP-1, and exploring ERK–RAR pathway cross-talk, including studying the mechanism of additive effect of the compounds in combination. Future work and cross-training will involve studying post-translational modifications and studying protein-protein interactions, including using chemical proteomics and structural biology. These areas will provide new insights into the mechanisms and translational potential of small molecule compounds targeting asthma pathology.

Notable publications and presentations:

  1. Marin, A., Taraban, M. B., Patel, V., Yu, Y. B., & Andrianov, A. K. (2022). Supramolecular Protein-Polyelectrolyte Assembly at Near Physiological Conditions-Water Proton NMR, ITC, and DLS Study. Molecules (Basel, Switzerland), 27(21), 7424.
  2. Patel, V.; Yu, J.; Weldemariam M.; Williams C.; Shapiro P.; Deshpande D.; Kane M. Dual Targeting of ERK1/2 and RARy: Functional Proteomics to Target Airway Remodeling in Asthma. Frontiers in the Chemistry Biology Interface Symposium (FCBIS). John’s Hopkins University, Baltimore, Maryland. May 2025. (oral talk)
  3. Patel, V.; Yu, J.; Weldemariam M.; Williams C.; Shapiro P.; Deshpande D.; Kane M. Vitamin A and ERK Signaling: A Dynamic Duo Against Asthma. American Society for Biochemistry and Molecular Biology (ASBMB) Annual Meeting. Chicago, Illinois. April 2025. (3 minute flash talk)
  4. Patel, V.; Yu, J.; Weldemariam M.; Williams C.; Shapiro P.; Deshpande D.; Kane M. Proteomic Profiling of RAR Agonist and ERK 1/2 Modulator in Asthma-Relevant Cell Model. American Society for Mass Spectrometry. Baltimore, Maryland. June 2025. (poster)

 

Jeanne Ngo

Iron is an essential nutrient for almost all living organisms, including pathogenic bacteria, as it plays critical roles in indispensable cellular processes including, but not limited to, electron transport, ATP synthesis, and DNA biosynthesis. Deprivation of iron can lead to the death of an organism, while an excess of iron can cause cellular damage. The presence of bioavailable iron contributes to the pathogenicity of bacteria. Therefore, it is essential to understand how iron homeostasis is maintained in order to use this mechanism to our advantage to fight antibacterial treatment-resistant infections. Despite how crucial iron is biologically, the acquisition of iron is non-trivial for bacteria. Within oxic environments, Fe(III) is the most prevalent oxidation state of iron, but itis highly insoluble. Within anoxic environments, Fe(II) is most prevalent and is significantly more soluble. Fe(III) transport systems are generally well understood, but the same cannot be said about Fe(II) transport systems. Feo is the most conserved and widely distributed system in prokaryotes that is dedicated to transporting Fe(II). Despite its importance in bacterial iron acquisition, the Feo system is poorly understood. In γ-proteobacteria, the Feo system is typically composed of three proteins: FeoA, FeoB, and FeoC. We have recently found that a new, small, Cys-rich membrane protein also exists in a mutually exclusive manner to FeoC. While FeoC is a small cytosolic proteins, this small, Cys-rich protein is located in the cytosolic membrane. Moreover, the main component of the Feo system is FeoB, a large transmembrane protein that moves Fe(II) across the lipid bilayer and is capable of NTP hydrolysis at its soluble N-terminal domain. My dissertation research investigates FeoC and FeoB’s metal-binding specificity toward first-row transition metals and explores the functional interactions between the new, small, Cys-rich membrane protein and FeoB, with the ultimate goal being to understand the mechanism of the Feo system in order to target this system for future therapeutic developments.

Notable publications and presentations:

  1. Ngo, J., et al. Metal Specificity of the ferrous iron protein C (FeoC). 2026 FCBIS Meeting. University of Delaware, Newark Delaware. May 2, 2026 (Poster)
  2. Ngo, J., et al. Metal Specificity of the ferrous iron protein C (FeoC). 2026 National ASBMB Meeting. Gaylord National Harbor Resort and Convention Center, Washington, DC. March 7-10, 2026 (Poster)
  3. Ngo, J.; Armstrong, C.M.; Smith, A.T. Metal-binding properties of the bacterial ferrous iron uptake (Feo) system. 2026. In preparation.

 

Sarah Pogash

Abnormal protein-protein interactions (PPI) contribute to the onset and progression of cancer. Acute leukemias are driven by rearrangements of the mixed-lineage leukemia (MLL) gene that result in the formation of oncogenic MLL fusion proteins. Menin, a classically defined tumor suppressor protein, abnormally interacts with MLL fusion proteins leading to leukemogenesis. PPI inhibitors have been developed to bind the menin protein and prevent its interaction with MLL, such as FDA-approved revumenib. However, long-term treatment with revumenib is limited by drug resistant mutations that are developed on menin ultimately interfering with the drug binding but not affecting the ability of menin to interact with MLL. Other PPI inhibitors targeting the menin-MLL interaction in clinical trials, such as ziftomenib, are presumed to also be limited by these drug-resistant mutations. Therefore, we propose to synthesize a library of menin degraders that are more robust against drug resistant mutations due to their event-driven pharmacology. PROteolysis TArgeting Chimeras (PROTACs) are a class of targeted protein degraders that utilize the ubiquitin proteasome system (UPS) to destroy disease-causing proteins. PROTACs feature a ligand that targets a protein of interest (POI) connected to a ligand that is recognized by an E3 ligase through a synthetic linker. A ternary complex is formed upon simultaneous binding of the POI and E3 ligase to the PROTAC initiating the polyubiquitination of the POI and subsequent degradation by the proteasome. Our menin PROTACs will be synthesized using a modified version of MI-853, a preclinical precursor of zoftomenib, as the POI ligand. We will connect our modified MI-853 to different variations of thalidomide through various synthetic linkers of different lengths. Our goal is to identify menin degraders that retain biological activity against cancer growth in both wild-type and drug-resistant acute leukemia cell lines.

Notable publications and presentations:

  1. Pogash, S. and Fletcher, S. Razing the Scaffold: The Elimination of Non-Catalytic Functions of Kinases through Targeted Protein Degradation. RSC Med. Chem. 2025. DOI: 10.1039/d5md00095e.
  2. Pogash, S. and Fletcher, S. Drugging the undruggable: Towards SNIPERs and covalent molecular glue degraders of aurora kinase A as indirect degraders of N-Myc and c-Myc. Frontiers in Chemistry and Biology Interface Symposium, Baltimore, Maryland, May 9, 2024.
  3. Pogash, S. and Fletcher, S. Drugging the undruggable: Towards SNIPERs and covalent molecular glue degraders of aurora kinase A as indirect degraders of N-Myc and c-Myc. American Chemical Society Fall Meeting, Denver, CO, Aug 18-22, 2024.