Biology subjects

Shumate, J.

Publications and source records attributed to Shumate, J..

3 recordsLinked to original sources

bioRxiv2026

Selective Glucocorticoid Receptor Modulators of Immune Checkpoint Function

Glucocorticoids (GCs) coordinate immunity, inflammation, and metabolism through allosteric regulation of the glucocorticoid receptor (GR) transcription factor. GCs are indispensable anti-inflammatory drugs yet linking specific ligand-receptor structural states to specific biological outcomes has remained a major barrier to designing safer, more selective therapies. Using structure-based design, we developed selective glucocorticoid receptor modulators (SGRMs) of immune function by extending a steroidal scaffold from the ligand-binding pocket into an adjacent solvent channel. These SGRMs suppressed T cell pro-inflammatory cytokines and promoted differentiation of memory precursor T cells while showing minimal induction of M2 macrophage polarization or T cell checkpoint proteins PD-1 and CTLA-4, all key targets of immunotherapy. Molecular dynamics simulations revealed that solvent-channel substituents function as a lever arm to drive dynamic oscillations in the steroid core, thereby allosterically tuning GR activity states. Systematic perturbation of immune cells with a graded series of ligands enabled a ligand perturbation with machine learning (LPML) framework to map coregulated responses across cell types and identified effector T cell gene networks tightly coupled with immune checkpoint induction. This approach outlines a general strategy for decoding the logic of allosteric drug action, enabling the rational design of SGRMs with tailored immunomodulatory profiles.

systems biology↗

bioRxiv2025

Discovery of a potent anti-Zika virus benzamide series targeting the viral protein NS4B

1.Zika virus (ZIKV), a member of the Flaviviridae family, causes significant public health concerns through congenital Zika syndrome and Guillain-Barre syndrome, yet no effective anti-ZIKV drugs or vaccines are available. To address this critical need, we conducted phenotypic, cytopathic effect-based, high-throughput screening followed by medicinal chemistry optimization and discovered novel benzamide anti-ZIKV leads. Current best compounds demonstrated superior potency (EC50 values 40-400 nM, CC50 > 50 {micro}M) compared to NITD-008, the most potent known anti-ZIKV agent. Time-of-addition assays, resistant virus selection studies, and biophysical binding experiments confirmed that NS4B interference constitutes the primary antiviral mechanism. Notably, resistance mutations mapped to the C-terminus of NS4B, distinct from other flavivirus NS4B inhibitors targeting dengue or yellow fever viruses, revealing novel insights into a critical function of the region. These findings establish NS4B as an Achilles heel for flaviviruses and support the development of pan-flavivirus therapeutics targeting this essential viral protein. 2. AUTHOR SUMMARYSince its pandemic spread in 2015-2016, Zika virus infection remains a significant public health threat worldwide. The virus can cause severe brain damage in developing babies and serious neurological complications like Guillain-Barre syndrome in adults. Despite these devastating consequences, we currently lack effective medicines or vaccines to prevent the virus from spreading through communities or from mothers to their unborn children. To address this critical gap, we conducted a large-scale screening of chemical compounds and discovered a promising new class of molecules that can effectively stop Zika virus from replication. Using medicinal chemistry techniques, we were able to make these compounds even more potent against the virus. In follow-up studies, we found that our compounds work by interfering with a specific viral protein called NS4B, which the virus needs to replicate its genome within the cell. Remarkably, other research teams studying related other flaviviruses (e.g., dengue and yellow fever virus) have independently discovered that this same protein is a vulnerable target. Our findings suggest that NS4B represents a universal weakness across the entire flavivirus family, making it an attractive target for developing broad-spectrum antiviral treatments.

microbiology↗

bioRxiv2025

The Endo-GeneScreen Platform Identifies Drug-Like Probes that Regulate Endogenous Protein Levels within Physiological Contexts

Traditional phenotypic drug discovery platforms have suffered from poor scalability and a lack of mechanistic understanding of newly discovered phenotypic probes. To address this, we created Endo-GeneScreen (EGS), a high-throughput enabled screening platform that identifies bioactive small molecules capable of regulating endogenous protein expression encoded by any preselected target gene within a biologically appropriate context. As a proof-of-concept, EGS successfully identified drug candidates that up-regulate endogenous expression of neuronal Syngap1, a gene that causes a neurodevelopmental disorder when haploinsufficient. For example, SR-1815, a previously unknown and undescribed kinase inhibitor, alleviated major cellular consequences of Syngap1 loss-of-function by restoring normal SynGAP protein levels and dampening neuronal hyperactivity within haploinsufficient neurons. Moreover, we demonstrate that EGS assays accelerate preclinical development of identified drug candidates and facilitate mode-of-action deconvolution studies. Thus, EGS identifies first-in-class bioactive small molecule probes that promote biological discovery and precision therapeutic development.

neuroscience↗