Biology subjects

Santhakumar, V.

Publications and source records attributed to Santhakumar, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Concussive Injury in Human Forebrain Organoids Alters Neurogenesis and Neuroimmune Signaling

Traumatic brain injury (TBI) is a major cause of long-term neurological disability, yet the mechanisms underlying human-specific injury responses remain poorly understood. Rodent models of TBI have yielded significant insights into mechanisms and pathophysiology of TBI but may not capture human-specific developmental and molecular responses. Here, we establish a human forebrain organoid (hFBO) injury paradigm to examine developmental stage and region-specific responses to concussive injury. Dorsal and ventral hFBOs, enriched in glutamatergic and GABAergic neurons, respectively, showed progressive physiological maturation with rudimentary firing characteristics at 80 days in vitro (DIV) and spontaneous synaptic activity by 150 DIV. Injury to dorsal and ventral hFBOs at 25 DIV, when neural progenitors dominate, caused cell death that scaled with severity and increased expression of neural proliferation markers and TLR4/NF-{kappa}B associated neuroimmune signaling. Injury to physiologically mature organoids at 150 DIV produced severity-dependent acute intracellular calcium dysregulation. Together, these findings establish a human organoid-based platform that captures developmental stage-dependent neurogenic, molecular, and cellular dysfunction in responses to concussive injury.

neuroscience↗

bioRxiv2026

Presynaptic GABABSignaling Enhances Synaptic Inhibition Without Mitigating Persistent Dentate Gyrus Hyperexcitability After Status Epilepticus

The dentate gyrus (DG) is a critical regulator of cortical input processing in the hippocampus, supporting spatial navigation and memory processing. In epilepsy, the DG undergoes extensive structural and functional reorganization that diminishes its ability to filter afferent inputs, resulting in enhanced hippocampal hyperexcitability, seizures, and cognitive impairment. Yet, how DG network dynamics evolve over time in the epileptic brain is not fully understood. Here, we investigated DG network excitability, feedback inhibition, and throughput in rats 1 week, 8 weeks, and 4 months after pilocarpine-induced status epilepticus (SE), and examined the role of presynaptic GABAB receptor-mediated modulation of DG activity. Recording from urethane-anesthetized rats in vivo, we show a persistent increase in excitation-spike (E-S) coupling after SE. In contrast, feedback inhibition measured by short-duration paired-pulse ratios (PPR at 20ms, 40 ms and 60ms intervals) was significantly increased 1 and 8 weeks after SE, but was indistinguishable from controls by 4 months. Notably, we found that dentate spike (DS) frequency remained persistently elevated up to 10 months post-SE. Selective inhibition of presynaptic GABAB receptors in the DG using CGP36216 further enhanced E-S coupling at 1 and 8 weeks in post-SE rats without affecting age-matched controls. CGP36216 did not alter E-S coupling in rats 4 months after SE, revealing a homeostatic role for basal presynaptic GABAB signaling in restraining network excitability early after SE. CGP36216 robustly increased PPR at 20ms across all groups without altering DS frequency, suggesting that GABAB receptors boost DG feedback inhibition. Mechanistically, CGP36216 reduced single stimulus-evoked inhibitory postsynaptic currents (eIPSCs) in dentate granule cells without altering excitatory transmission after SE. Together, these findings support a disinhibitory role for presynaptic GABAB receptors, which bolsters synaptic inhibition to transiently counter post-SE hyperexcitability, and offers a targetable mechanism for therapeutic intervention during epileptogenesis.

neuroscience↗

bioRxiv2026

An Atlas of Short Linear Motif-Mediated Human Protein-Protein Interactions

Short linear motifs (SLiMs) within intrinsically disordered protein regions mediate transient interactions crucial for cell physiology1. However, the global interaction landscape of human SLiMs remains largely uncharted. Here we present the Atlas of SLiM-mediated Human protein-protein Interactions (ASHI), which maps more than 20,000 interactions by screening over 800 human protein domains against a library of one million peptides tiling the human disordered proteome. ASHI expands the SLiM interactome, uncovers novel binding modes for known peptide-binding domains, and reveals unexpected peptide-binding activities in enzymes, chaperones, RNA-binding proteins, and modification-reader domains. Furthermore, intrinsically disordered regions emerge as densely encoded interaction platforms where interaction specificity is governed by diverse mechanisms, including key motif determinants, flanking residues, competition, and multivalency. These data provide an unprecedented foundation for modeling dynamic interaction networks, interpreting disease-associated variants, and decoding the dark proteome.

biochemistry↗

bioRxiv2026

Passive neuromodulation: an energy-driven mechanism for closed-loop suppression of epileptic seizure

For decades, electrical neuromodulation has been used as a therapeutic mechanism to disrupt and desynchronize pathological neural activity in various neurological disorders. Despite notable progress, however, patient outcomes remain highly variable, particularly in medically intractable epilepsy where surgery still provides the greatest chance of seizure freedom. Here we propose passive neuromodulation (PNM) as a radical alternative to conventional neurostimulation, whereby analogue feedback is used to drain energy from an epileptic circuit and thus suppress the initiation or spread of electrographic seizures. We provide pilot evidence on the efficacy and robustness of PNM using two computational models of epileptic dynamics: a detailed biophysical network model of dentate gyrus, and the Epileptor neural mass model of seizure dynamics. Despite the vast differences between these models, our results show the robust ability of PNM to suppress seizures in both models. We further demonstrate the efficacy and robustness of responsive PNM, whereby brief (50ms) windows of PNM are triggered by a simultaneously-running seizure detection algorithm, as well as the safe and tunable nature of PNM, where more robust seizure suppression can be achieved by parametrically titrating the amount of power drained from the tissue, without inducing any seizures even if applied interictally. Overall, our results provide strong evidence on the promise of PNM for the closed-loop control of epileptic seizures and other neurological disorders where damping pathological network activity can restore healthy dynamics.

neuroscience↗

bioRxiv2026

Determination of the cellular target engagement by direct-to-biology Cellular Thermal Shift Assay (CETSA)

The direct-to-biology approach enables rapid, high-throughput evaluation of large compound libraries in biological assays, eliminating costly and time-consuming purification steps. This strategy has been widely used in the development of proteolysis-targeting chimeras (PROTACs) to facilitate rapid linker optimization and the identification of active degraders from thousands of crude candidate compounds. Similarly, some other direct-to-biology biophysical assays have been utilized for the optimization of small-molecule ligands. However, a direct-to-biology strategy for evaluating cellular target engagement has not yet been demonstrated. Here, we extend this approach to the cellular thermal shift assay (CETSA). By systematically comparing crude reaction mixtures of reported DCAF11 covalent ligands with their corresponding purified analogues, we demonstrate that unpurified compounds can be directly evaluated in CETSA to assess cellular target engagement.

cell biology↗

bioRxiv2026

Direct-to-Biology Enables Rapid Identification of Potent FBXO22 Degraders

Proteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules that bring a ubiquitin E3 ligase into proximity of a target protein to polyubiquitinate and degrade the target. PROTACs act catalytically, offering distinct advantages over conventional inhibitors and are the subject of intense study. The development of PROTACs involves extensive optimization of the chemical moiety linking two different protein-binding chemotypes, often requiring the synthesis, purification and testing of hundreds of PROTAC candidates. We used this approach to rapidly explore the landscape of targeted degradation of four different targets in parallel, combining and comparing a recently reported FBXO22-recruiting chemical warhead with warheads for the commonly used CRBN and VHL E3 ligases. Using a limited number of compounds (175 compounds in total) we observed no FBXO22-dependent degradation of these four targets. However, our libraries generated potent FBXO22 homo-PROTACs inducing self-degradation, as well as CRBN- and VHL-mediated degraders of FBXO22.

cell biology↗

bioRxiv2026

Altered Physiology and Ensemble Recruitment of Dentate Gyrus Semilunar Granule Cells in a Mouse Model of Epilepsy

The dentate gyrus is a major locus for structural and synaptic reorganization in temporal lobe epilepsy. While physiological changes during epileptogensis are well characterized in the principal dentate projection neuron, granule cells (GCs), epilepsy-related changes in semilunar granule cells (SGCs), a distinct subset of dentate projection neurons, remain unknown. Using a mouse pilocarpine model of epilepsy, we show that, unlike GCs, SGCs exhibit an increase in intrinsic excitability 1 week after status epilepticus (SE). GCs, not SGCs. have a lower threshold for action potential firing in mice 1-month post-SE. Both GCs and SGCs display increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) 1-week and 1-month after SE. Uniquely, SGCs received more frequent spontaneous inhibitory postsynaptic currents (sIPSCs) and exhibited smaller afferent-evoked IPSCs early after SE. Additionally, evoked EPSC amplitude in SGCs was reduced 1-month post-SE. Behaviorally, mice 1-month post-SE showed impairments in their ability to use spatial search strategies in a Barnes maze paradigm. Post-SE TRAP2::tdT mice showed reduced activity dependent neuronal ensemble labeling, with fewer tdT-labeled neurons in both task-naive and trained conditions and reduced c-Fos co-expression following task re-acquisition compared to controls. Notably, the proportion of SGCs within labeled ensembles was reduced in task-naive epileptic mice but not in trained animals. Collectively, our findings identify selective changes in SGC intrinsic excitability during epileptogenesis that could contribute to enhanced network excitability. The cell-specific alterations in SGC circuit connectivity during epileptogenesis, alongside the apparent reduction in neuronal recruitment to behavioral ensembles likely contribute to spatial navigation deficits observed in epilepsy.

neuroscience↗

bioRxiv2026

Neuronal Toll-like Receptor-4 regulation of Matrix Metalloproteinase-9 Activity Mediates Dentate Circuit Dysfunction after Traumatic Brain Injury

Neuroinflammatory pathways activated by traumatic brain injury (TBI) are critical mediators of long-term neurological dysfunction and represent promising therapeutic targets. Toll-like receptor 4 (TLR4), an innate immune receptor, was previously shown to contribute to increased seizure susceptibility and cognitive deficits in rats after lateral fluid percussion injury (FPI). However, the cellular and molecular mechanisms underlying TLR4-mediated circuit dysfunction early after brain injury are not fully understood. In this study, we define a cell- and circuit-specific neuroimmune-enzyme effector signaling axis that mediates early post-TBI circuit dysfunction in the hippocampal Dentate Gyrus (DG). Using ex vivo electrophysiology in rat and mouse models one-week after brain injury, we demonstrate that neuronal TLR4 signaling regulates both excitatory and inhibitory synaptic inputs to dentate granule cells (DGC). Collectively, pharmacological inhibition of TLR4 in rats and cell-type-specific deletion of TLR4 in mice show that neuronal TLR4 mediates injury-driven increase in DGC excitatory input frequency and relies on downstream activation of Matrix Metalloproteinase-9 (MMP-9). In contrast, TLR4 signaling contributed to decrease in inhibitory current frequency after injury, but independent of MMP-9, revealing a mechanistic divergence. Systemic inhibition of either TLR4 signaling or MMP-9 activity in rats within 24 hours after injury reduced network hyperexcitability and improved long-term potentiation (LTP) in the DG measured in vivo one-week after injury. Either TLR4 or MMP-9 inhibition early after injury effectively attenuated spatial memory deficits in a Barnes maze task one-month post-injury. Paradoxically, in sham controls, inhibition of TLR4 increased frequency of both excitatory and inhibitory inputs to DGCs and augmented network excitability, without altering MMP-9 levels, identifying context-dependent roles for TLR4 signaling. Together, these results identify a novel TLR4-MMP-9 axis as a key driver of early post-TBI dentate gyrus circuit dysfunction and behavioral deficits.

neuroscience↗

bioRxiv2025

Development of a dual chemical probe for the USP16 and HDAC6 zinc-finger ubiquitin-binding domain

Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that specifically cleaves ubiquitin from histone H2A, and modulates gene expression, cell cycle regulation, and various other cellular processes. The USP16 zinc-finger ubiquitin-binding domain (UBD) binds the free C-terminal end of both ubiquitin and ISG15, two major signaling proteins that mediate many biological pathways. Because the precise function of USP16-UBD and its interactions remains unclear, a small molecule antagonist targeting the USP16-UBD could enable cellular studies to elucidate its biological role. Here we report SGC-UBD1031 (15), a chemical probe targeting USP16-UBD with similar in vitro binding profiles to HDAC6-UBD and selectivity over nine other UBDs. In cellular assays, 15 disrupts the interaction between the C-terminus of ISG15 and USP1-UBD, as well as the interaction between ISG15 and HDAC6 UBD, at a concentration of 1 M. The corresponding enantiomer SGC-UBD1031N (16), does not interfere with these interactions, even at concentrations as high as 30 M, and thus serves as a negative control. Table of Contents graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/684218v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@50def6org.highwire.dtl.DTLVardef@15dedc4org.highwire.dtl.DTLVardef@1a50169org.highwire.dtl.DTLVardef@1ffbb4b_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Differential Glutamatergic Inputs to Semilunar Granule Cells and Granule Cells Underscore Dentate Gyrus Projection Neuron Diversity

Semilunar Granule Cells (SGCs) are sparse dentate gyrus projection neurons whose role in the dentate circuit, including pathway specific inputs, remains unknown. We report that SGCs receive more frequent spontaneous excitatory synaptic inputs than granule cells (GCs). Dual GC-SGC recordings identified that SGCs receive stronger medial entorhinal cortex and associational synaptic drive but lack short-term facilitation of lateral entorhinal cortex inputs observed in GCs. SGCs dendritic spine density in proximal and middle dendrites was greater than in GCs. However, the strength of commissural inputs and dendritic input integration, examined in passive morphometric simulations, were not different between cell types. Activity dependent labeling identified an overrepresentation of SGCs among neuronal ensembles in both mice trained in a spatial memory task and task naive controls. The divergence of modality specific inputs to SGCs and GCs can enable parallel processing of information streams and expand the computational capacity of the dentate gyrus.

neuroscience↗

bioRxiv2025

Enantioselective Protein Affinity Selection Mass Spectrometry (EAS-MS)

We report an enantioselective protein affinity selection mass spectrometry screening approach (E-ASMS) that enables the detection of weak binders, informs on selectivity, and generates orthogonal confirmation of binding. After method development with control proteins, we screened 31 human proteins against a designed library of 8,210 chiral compounds. 16 binders to 12 targets, including many proteins predicted to be "challenging to ligand", were discovered and confirmed in orthogonal biophysical assays. 7 binders to 6 targets bound in an enantioselective manner, with KD values ranging from 3 to 20 {micro}M. Binders for four targets (DDB1, WDR91, WDR55, and HAT1) were selected for in-depth characterization using X-ray crystallography. In all four cases, the mechanism for enantioselectivity was readily explained. We conclude E-ASMS can be used to identify and characterize selective and weakly-binding ligands for novel protein targets with unprecedented throughput and sensitivity.

pharmacology and toxicology↗

bioRxiv2024

Cellular and circuit features distinguish dentate gyrus semilunar granule cells and granule cells activated during contextual memory formation

The dentate gyrus is critical for spatial memory formation and shows task related activation of cellular ensembles considered as memory engrams. Semilunar granule cells (SGCs), a sparse dentate projection neuron subtype distinct from granule cells (GCs), were recently reported to be enriched among behaviorally activated neurons. However, the mechanisms governing SGC recruitment during memory formation and their role in engram refinement remains unresolved. By examining neurons labeled during contextual memory formation in TRAP2 mice, we empirically tested competing hypotheses for GC and SGC recruitment into memory ensembles. In support of the proposal that more excitable neurons are preferentially recruited into memory ensembles, SGCs showed greater sustained firing than GCs. Additionally, SGCs labeled during memory formation showed less adapting firing than unlabeled SGCs. Our recordings did not reveal glutamatergic connections between behaviorally labeled SGCs and GCs, providing evidence against SGC driven local circuit feedforward excitation in ensemble recruitment. Contrary to a leading hypothesis, there was little evidence for individual SGCs or labeled neuronal ensembles supporting lateral inhibition of unlabeled neurons. Instead, labeled GCs and SGCs received more spontaneous excitatory synaptic inputs than their unlabeled counterparts. Moreover, pairs of GCs and SGCs within labeled neuronal cohorts received more temporally correlated spontaneous excitatory synaptic inputs than labeled-unlabeled neuronal pairs, validating a role for correlated afferent inputs in neuronal ensemble selection. These findings challenge the proposal that SGCs drive dentate GC ensemble refinement, while supporting a role for intrinsic active properties and correlated inputs in preferential SGC recruitment to contextual memory engrams. Impact StatementEvaluation of semilunar granule cell involvement in dentate gyrus contextual memory processing supports recruitment based on intrinsic and input characteristics while revealing limited contribution to ensemble refinement. Major subject area, keywords and organismsSemilunar granule cell, inhibition, memory, engram, circuit, hippocampus

neuroscience↗

bioRxiv2024

A resource to enable chemical biology and drug discovery of WDR Proteins

Protein class-focused drug discovery has a long and successful history in pharmaceutical research, yet most members of druggable protein families remain unliganded, often for practical reasons. Here we combined experiment and computation to enable discovery of ligands for WD40 repeat (WDR) proteins, one of the largest human protein families. This resource includes expression clones, purification protocols, and a comprehensive assessment of the druggability for hundreds of WDR proteins. We solved 21 high resolution crystal structures, and have made available a suite of biophysical, biochemical, and cellular assays to facilitate the discovery and characterization of small molecule ligands. To this end, we use the resource in a hit-finding pilot involving DNA-encoded library (DEL) selection followed by machine learning (ML). This led to the discovery of first-in-class, drug-like ligands for 9 of 20 targets. This result demonstrates the broad ligandability of WDRs. This extensive resource of reagents and knowledge will enable further discovery of chemical tools and potential therapeutics for this important class of proteins.

biochemistry↗

bioRxiv2024

Dysregulation of Neuropilin-2 Expression in Inhibitory Neurons Impairs Hippocampal Circuit Development Leading to Autism-Epilepsy Phenotype

Dysregulation of development, migration, and function of interneurons, collectively termed interneuronopathies, have been proposed as a shared mechanism for autism spectrum disorders (ASDs) and childhood epilepsy. Neuropilin-2 (Nrp2), a candidate ASD gene, is a critical regulator of interneuron migration from the median ganglionic eminence (MGE) to the pallium, including the hippocampus. While clinical studies have identified Nrp2 polymorphisms in patients with ASD, whether selective dysregulation of Nrp2-dependent interneuron migration contributes to pathogenesis of ASD and enhances the risk for seizures has not been evaluated. We tested the hypothesis that the lack of Nrp2 in MGE-derived interneuron precursors disrupts the excitation/inhibition balance in hippocampal circuits, thus predisposing the network to seizures and behavioral patterns associated with ASD. Embryonic deletion of Nrp2 during the developmental period for migration of MGE derived interneuron precursors (iCKO) significantly reduced parvalbumin, neuropeptide Y, and somatostatin positive neurons in the hippocampal CA1. Consequently, when compared to controls, the frequency of inhibitory synaptic currents in CA1 pyramidal cells was reduced while frequency of excitatory synaptic currents was increased in iCKO mice. Although passive and active membrane properties of CA1 pyramidal cells were unchanged, iCKO mice showed enhanced susceptibility to chemically evoked seizures. Moreover, iCKO mice exhibited selective behavioral deficits in both preference for social novelty and goal-directed learning, which are consistent with ASD-like phenotype. Together, our findings show that disruption of developmental Nrp2 regulation of interneuron circuit establishment, produces ASD-like behaviors and enhanced risk for epilepsy. These results support the developmental interneuronopathy hypothesis of ASD epilepsy comorbidity.

neuroscience↗

bioRxiv2023

Chemical Tools for the Gid4 Subunit of the Human E3 Ligase C-terminal to LisH (CTLH) Degradation Complex

We have developed a novel chemical handle (PFI-E3H1) and a chemical probe (PFI-7) as ligands for the Gid4 subunit of the human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) and leveraging the sizeable Pfizer compound library, we identified a 500 nM ligand for this E3 ligase through file screening alone. Further exploration identified a vector that is tolerant to addition of a linker for future chimeric molecule design. The chemotype was subsequently optimized to sub-100 nM Gid4 binding affinity for a chemical probe. These novel tools, alongside the suitable negative control also identified, should enable the interrogation of this complex human E3 ligase macromolecular assembly.

biophysics↗

bioRxiv2023

RECLUSIVE CHANDELIERS: FUNCTIONAL ISOLATION OF DENTATE AXO-AXONIC CELLS AFTER EXPERIMENTAL STATUS EPILEPTICUS

Axo-axonic cells (AACs) provide specialized inhibition to the axon initial segment (AIS) of excitatory neurons and can regulate network output and synchrony. Although hippocampal dentate AACs are structurally altered in epilepsy, physiological analyses of dentate AACs are lacking. We demonstrate that parvalbumin neurons in the dentate molecular layer express PTHLH, an AAC marker, and exhibit morphology characteristic of AACs. Dentate AACs show high-frequency, non-adapting firing but lack persistent firing in the absence of input and have higher rheobase than basket cells suggesting that AACs can respond reliably to network activity. Early after pilocarpine-induced status epilepticus (SE), dentate AACs receive fewer spontaneous excitatory and inhibitory synaptic inputs and have significantly lower maximum firing frequency. Paired recordings and spatially localized optogenetic stimulation revealed that SE reduced the amplitude of unitary synaptic inputs from AACs to granule cells without altering reliability, short-term plasticity, or AIS GABA reversal potential. These changes compromised AAC-dependent shunting of granule cell firing in a multicompartmental model. These early post-SE changes in AAC physiology would limit their ability to receive and respond to input, undermining a critical brake on the dentate throughput during epileptogenesis.

neuroscience↗

bioRxiv2023

Electrical Coupling between Parvalbumin Basket Cells is Reduced after Experimental Status Epilepticus

Acquired epilepsies, characterized by abnormal increase in hypersynchronous network activity, can be precipitated by various factors including brain injuries which cause neuronal loss and increases in network excitability. Electrical coupling between neurons, mediated by gap junctions, has been shown to enhance synchronous neuronal activity and promote excitotoxic neurodegeneration. Consequently, neuronal gap junctional coupling has been proposed to contribute to development of epilepsy. Parvalbumin expressing interneurons (PV-INs), noted for their roles in powerful perisomatic inhibition and network oscillations, have gap junctions formed exclusively by connexin 36 subunits which show changes in expression following seizures, and in human and experimental epilepsy. However, only a fraction of the connexin hemichannels form functional connections, leaving open the critical question of whether functional gap junctional coupling between neurons is altered during development of epilepsy. Using a pilocarpine induced status epilepticus (SE) model of acquired temporal lobe epilepsy in rat, this study examined changes in electrical coupling between PV-INs in the hippocampal dentate gyrus one week after SE. Contrary to expectations, SE selectively reduced the probability of electrical coupling between PV-INs without altering coupling coefficient. Both coupling frequency and coupling coefficient between non-parvalbumin interneurons remained unchanged after SE. The early and selective decrease in functional electrical coupling between dentate PV-INs after SE may represent a compensatory mechanism to limit excitotoxic damage of fast-spiking interneurons and network synchrony during epileptogenesis.

neuroscience↗

bioRxiv2023

Discovery of a first-in-class small molecule ligand for WDR91 using DNA-encoded chemical library selection followed by machine learning

WD40 repeat-containing protein 91 regulates endosomal phosphatidylinositol 3-phosphate levels at the critical stage of endosome maturation and plays vital roles in endosome fusion, recycling, and transport by mediating protein-protein interactions. Due to its various roles in endocytic pathways, WDR91 has recently been identified as a potential host factor responsible for viral infection. We employed DNA-Encoded Chemical Library (DEL) selection against the WDR domain of WDR91, followed by machine learning to generate a model that was then used to predict ligands from the synthetically accessible Enamine REAL database. Screening of predicted compounds enabled us to identify the hit compound 1, which binds selectively to WDR91 with a KD of 6 {+/-} 2 M by surface plasmon resonance. The co-crystal structure confirmed the binding of 1 to the WDR91 side pocket, in proximity to cysteine 487. Machine learning-assisted structure activity relationship-by-catalog validated the chemotype of 1 and led to the discovery of covalent analogs 18 and 19. Intact mass LC-MS and differential scanning fluorimetry confirmed the formation of a covalent adduct, and thermal stabilization, respectively. The discovery of 1, 18, 19, accompanying SAR, and co-crystal structures will provide valuable insights for designing more potent and selective compounds against WDR91, thus accelerating the development of novel chemical tools to evaluate the therapeutic potential of WDR91 in disease.

molecular biology↗