UBA5 is the E1 enzyme that initiates UFMylation, a ubiquitin-like modification implicated in proteostasis, neurodegeneration, and cancer. Here, we report a chemical biology approach to interrogate UBA5 function through small-molecule inhibition. We developed a robust high-throughput screening assay based on AMP-GloTM and screened a library of blood-brain barrier-permeable compounds, identifying five inhibitors spanning three distinct scaffolds with low-micromolar potency. Orthogonal biochemical and gel-based assays confirmed that these compounds directly inhibit UBA5-mediated UFM1 activation and conjugation, with selectivity over other E1 enzymes, including UBA1. In cells, these compounds suppressed endogenous UFMylation without significantly affecting global polyubiquitination, supporting pathway and target engagement. Together, these studies establish UBA5 as a tractable enzymatic target and provide first-in-class chemical tools to probe UFMylation. Given the emerging role of UFMylation in disease, these inhibitors offer a foundation for developing therapeutics targeting proteostasis pathways.
Vigyasa Singh, Yuansong Wan, Zhisong Gao et al.· ACS Chemical Biology· 0 citations
Human respiratory viruses represent a major global health burden, causing millions of severe infections and deaths annually. Despite the central role of vaccines in prevention, their limitations, such as incomplete coverage, waning immunity, and vulnerability to viral evolution, underscore the urgent need for effective antiviral therapeutics. This review examines the principles and applications of target-based antiviral drug development against human respiratory viruses, emphasizing the identification and exploitation of conserved viral and host targets. Key viral proteins, including RNA-dependent RNA polymerases, proteases, and fusion glycoproteins, are analyzed across major virus families such as coronaviruses, paramyxoviruses, and adenoviruses, highlighting their structural features, functional constraints, and therapeutic potential. We further explore the integration of high-throughput screening and rational drug design, supported by advances in structural biology, cryo-electron microscopy, and computational approaches, including artificial intelligence-driven drug discovery. These methodologies collectively enhance the precision and efficiency of antiviral development. However, significant challenges remain, particularly the conflict between viral mutation and target conservation, the rapid emergence of drug resistance, and the safety limitations of host-targeted therapies. Finally, we discuss emerging strategies to overcome these barriers, including combination therapies and the development of broad-spectrum antivirals targeting conserved molecular mechanisms. This paper highlights a framework for the rational design of durable antiviral interventions capable of addressing both existing and emerging respiratory viral threats.
S. Samrat, Gaurie Srivastava, Ran Zhang et al.· Pathogens· 0 citations
The expression, purification, and enzymatic characterization of recombinant Mtb ADSS are reported, providing the first comprehensive biochemical framework for studying Mtb ADSS and establishing a foundation for structure-guided inhibitor discovery targeting purine biosynthesis as a novel antitubercular strategy.
Vigyasa Singh, Ran Zhang, Ke Chen et al.· Biochimica et Biophysica Act...· 0 citations
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