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).

Melanie Nelson

Human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs) are small, lipid-bound particles that carry bioactive molecules reflective of the state of their parent cells and play a critical role in the regenerative and immunomodulatory functions of hMSCs. As therapeutic agents, EVs offer several advantages over cell-based therapies, including low immunogenicity, the inability to self-replicate, and as natural delivery vehicles capable of crossing biological barriers including the blood-brain barrier. Previous studies have shown that culturing hMSCs on biomimetic substrates enhances cell proliferation, adhesion, and cytokine expression compared with conventional tissue culture plastic. My project investigates whether biomimetic polymeric multilayers composed of heparin and collagen, fabricated using layer-by-layer (LbL) assembly through electrostatic interactions, would similarly enhance hMSC extracellular vesicle production. Currently, my findings suggest the physical and biochemical properties of culture substrates significantly influence both the yield and molecular content of hMSC-derived EVs. These results demonstrate the potential of biomimetic LbL culture platforms to improve EV production and support the development of scalable EV-based regenerative therapies.

Notable publications and presentations:

  1. Nelson, Melanie; Wilson-Gray, A.; Hofstetter, S.; Cottingham, A.; Pearson, R; Almodovar, J.; Heparin/Collagen Multilayers Affect Extracellular Vesicle Production in Human Mesenchymal Stem Cells. American Institute of Chemical Engineers Annual Meeting (November 2025). (Oral Presentation)
  2. Coming soon!
  3. Coming soon!

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.

 

Vincent Lowe

Bridging the gap between experimental results and computational data/predictions has been a longstanding focus of scientific research in various fields and applications. The focus on bridging this gap has only been catalyzed by the advent and continuous improvement of various machine learning models in areas such as cancer identification, structural prediction, and language models. The ability to train an algorithm with highly complex data to derive patterns and predictions provides scientists with tools to empirically quantify previously qualitative or unknown information. Currently there still exists a gap of knowledge in the field of proteins when it comes to understanding or deriving quantitative measurements of the dynamics and high-resolution structural information. One structural biology method that provides insight into structure and dynamics factor of proteins is hydrogen–deuterium exchange coupled with mass spectrometry (HDX-MS). HDX-MS provides a lens in which to study protein dynamics and structure in solution, by monitoring the exchange of the backbone amide hydrogen with solvent deuterium as a function of time. However, even though HDX-MS provides information that is spatially and temporally resolved, it remains limited in its resolution, providing data that is typically at the peptide level resolution. The integration with computational methodologies can allow for the extraction of atom level, high resolution, structural and dynamics information from HDX-MS data making it ideal for its use within machine learning models. To this end, the overarching goal of my research is to expand upon the empirical understanding of HDX-MS data using machine learning models and integrative approaches to allow the development of optimized workflows characterizing conformational landscapes, allostery, protein-ligand interactions, macromolecular interactions, and the factors that influence protection from exchange

Notable publications and presentations:

  1. Kihn, K. C.; Purdy, O.; Lowe, V.; Slachtova, L.; Smith, A. K.; Shapiro, P.; Deredge, D. J. Integration of Hydrogen–Deuterium Exchange Mass Spectrometry with Molecular Dynamics Simulations and Ensemble Reweighting Enables High Resolution Protein–Ligand Modeling. J. Am. Soc. Mass. Spec. 2024, 35 (11), 2714–2728.
  2. Marshall, P.; Lowe, V. M.; Gao, Y.; Glarborg, P. The Reaction Rates of Amidogen and Ammonia with Nitrous Oxide: Implications for Combustion Mechanisms. J. Phys. Chem. A. 2025, 129 (38), 8858-8867
  3. Lowe, V. M., Parka, R., Toci, E., Meyers. C. F., Deredge, D. J. Leveraging Hydrogen Deuterium Exchange Mass Spectrometry Data and Machine Learning to Refine Protein-Ligand Docking Pose Selection. 5th International Conference on Hydrogen Deuterium Exchange Mass Spectrometry. March 2026. (Poster)