Biology subjects

Zhou, J.

Publications and source records attributed to Zhou, J..

At least 469 records · Page 26Linked to original sources

bioRxiv2021

Representation of Drosophila larval behaviors by muscle activity patterns

How muscle actions are coordinated to realize animal movement is a fundamental question in behavioral study. To obtain the overall muscular activity patterns accompanying behaviors at high spatiotemporal resolution is technically difficult. In this work, we used light sheet microscopy to simultaneously image and analyze the activity, length and orientation of Drosophila larval muscles across body segments at single muscle resolution in nearly free behaviors. For typical behavioral modes such as peristalsis, head cast and turning, larval muscles showed behavioral mode specific activity patterns. Unexpectedly, reorientation of larval head involves muscle tone in the apparently motionless posterior segments. With a STGCN(spatial temporal graph convolution neural network)-Generator model, sequence of larval behavioral poses outlined by morphological patterns of muscles could be accurately predicted based on the time series of ventral but not dorsal muscle activities, and vice versa. Laser ablation of ventral but not dorsal muscles interrupted peristaltic wave and undermined head cast in both frequency and amplitude. Our results provide a simplified muscle activity representation of soft body motion that can be used for probing the key components of animal motor control.

neuroscience↗

bioRxiv2021

A human monoclonal antibody potently pan-neutralizes SARS-CoV-2 VOCs by targeting RBD invariant sites

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of novel corona virus disease (COVID-19). The neutralizing monoclonal antibodies (mAbs) targeting the receptor binding domain (RBD) of SARS-CoV-2 are among the most promising strategies to prevent and treat COVID-19. However, SARS-CoV-2 variants of concern (VOCs) profoundly reduced the efficacies of most of mAbs and vaccines approved for clinical use. Herein, we demonstrated mAb 35B5 efficiently neutralizes both wild-type (WT) SARS-CoV-2 and VOCs, including B.1.617.2 (delta) variant, in vitro and in vivo. Cryo-electron microscopy (cryo-EM) revealed that 35B5 neutralizes SARS-CoV-2 by targeting a unique epitope that avoids the prevailing mutation sites on RBD identified in circulating VOCs, providing the molecular basis for its pan-neutralizing efficacy. The 35B5-binding epitope could also be exploited for the rational design of a universal SARS-CoV-2 vaccine.

immunology↗

bioRxiv2021

Identifying Microbial Interaction Networks Based on Irregularly Spaced Longitudinal 16S rRNA sequence data

The microbial interactions within the human microbiome are complex and temporally dynamic, but few methods are available to model this system within a longitudinal network framework. Based on general longitudinal 16S rRNA sequence data, we propose a stationary Gaussian graphical model (SGGM) for microbial interaction networks (MIN) which can accommodate the possible correlations between the high-dimensional observations. For SGGM, an EM-type algorithm is devised to compute the L1-penalized maximum likelihood estimate of MIN which employs the classic graphical LASSO algorithm as the building block and can therefore be implemented easily. Simulation studies show that the proposed algorithms can significantly outperform the conventional algorithms when the correlations between measurements grow large. The algorithms are then applied to a real 16S rRNA gene sequence data set for gut microbiome. With the estimated MIN in hand, module-preserving permutation test is proposed to test the independence of the MIN and the corresponding phylogenetic tree. The results demonstrate strong evidence of an association between the MIN and the phylogenetic tree which indicates that the genetically related taxa tend to have more/stronger interactions. The proposed algorithms are implemented in R package lglasso at https://CRAN.R-project.org/package=lglasso.

bioinformatics↗

bioRxiv2021

Neurotoxic Amyloidogenic Peptides Identified in the Proteome of SARS-COV2: Potential Implications for Neurological Symptoms in COVID-19

COVID-19 is primarily known as a respiratory disease caused by the virus SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe headaches, and even stroke are reported in as many as 30% of cases and can persist even after the infection is over (so-called long COVID). These neurological symptoms are thought to be caused by brain inflammation, triggered by the virus infecting the central nervous system of COVID-19 patients, however we still dont fully understand the mechanisms for these symptoms. The neurological effects of COVID-19 share many similarities to neurodegenerative diseases such as Alzheimers and Parkinsons in which the presence of cytotoxic protein-based amyloid aggregates is a common etiological feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we performed a bioinformatic scan of the SARS-CoV-2 proteome, detecting peptide fragments that were predicted to be highly amyloidogenic. We selected two of these peptides and discovered that they do rapidly self-assemble into amyloid. Furthermore, these amyloid assemblies were shown to be highly toxic to a neuronal cell line. We introduce and support the idea that cytotoxic amyloid aggregates of SARS-CoV-2 proteins are causing some of the neurological symptoms commonly found in COVID-19 and contributing to long COVID, especially those symptoms which are novel to long COVID in contrast to other post-viral syndromes.

biochemistry↗

bioRxiv2021

Parapatric speciation with recurrent gene flow of two sexual dichromatic pheasants

BackgroundUnderstanding speciation has long been a fundamental goal of evolutionary biology. It is widely accepted that speciation requires an interruption of gene flow to generate strong reproductive isolation between species, in which sexual selection may play an important role by generating and maintaining sexual dimorphism. The mechanism of how sexual selection operated in speciation with gene flow remains an open question and the subject of many research. Two species in genus Chrysolophus, Golden pheasant (C. pictus) and Lady Amhersts pheasant (C. amherstiae), which both exhibit significant plumage dichromatism, are currently parapatric in the southwest China with several hybrid recordings in field. MethodsIn this research, we estimated the pattern of gene flow during the speciation of two pheasants using the Approximate Bayesian Computation (ABC) method based on the multiple genes data. With a new assembled de novo genome of Lady Amhersts pheasant and resequencing of widely distributed individuals, we reconstructed the demographic history of the two pheasants by pairwise sequentially Markovian coalescent (PSMC). ResultsThe results provide clear evidence that the gene flow between the two pheasants were consistent with the prediction of isolation with migration model for allopatric populations, indicating that there was long-term gene flow after the initially divergence (ca. 2.2 million years ago), and further support the secondary contact when included the parapatric populations since around 30 ka ongoing gene flow to now, which might be induced by the population expansion of the Golden pheasant in late Pleistocene. ConclusionsThe results of the study support the scenario of speciation between Golden pheasant (C. pictus) and Lady Amhersts pheasant (C. amherstiae) with cycles of mixing-isolation-mixing due to the dynamics of natural selection and sexual selection in late Pleistocene that provide a good research system as evolutionary model to test reinforcement selection in speciation.

evolutionary biology↗

bioRxiv2021

Estrogen-related receptor alpha and Rplp1 ribosome protein-dependent translation coordinately regulate starvation response and decrease NASH progression

BackgroundCurrently, little is known about the mechanism(s) regulating global and specific protein translation during non-alcoholic steatohepatitis (NASH). MethodsWe used puromycin-labelling, polysome profiling, ChIPseq and ChIP-qPCR, and gene manipulation in vitro and in dietary mouse models of NASH in this study. ResultsUsing unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling, we observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of NASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in NASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Essra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of NASH. ConclusionEsrra regulation of Rplp1-mediated translation of lysosome / autolysosome proteins was downregulated during NASH. Alternate day fasting activated this novel pathway and improved NASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for NASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.

molecular biology↗

bioRxiv2021

Inhibition of BET family proteins suppresses African swine fever virus infection

African swine fever (ASF), an acute, severe, highly contagious disease caused by African swine fever virus (ASFV) infection in domestic pigs and boars, has a mortality rate of up to 100%. Because effective vaccines and treatments for ASF are lacking, effective control of the spread of ASF remains a great challenge for the pig industry. Host epigenetic regulation is essential for the viral gene transcription. Bromodomain and extraterminal (BET) family proteins, including BRD2, BRD3, BRD4, and BRDT, are epigenetic "readers" critical for gene transcription regulation. Among these proteins, BRD4 recognizes acetylated histones via its two bromodomains (BD1 and BD2) and recruits transcription factors, thereby playing a pivotal role in transcriptional regulation and chromatin remodeling during viral infection. However, how BET/BRD4 regulates ASFV replication and gene transcription is unknown. Here, we randomly selected 12 representative BET family inhibitors and compared their effects on ASFV infection in pigs primary alveolar macrophages (PAMs). They were found to inhibit viral infection by interfering with the different stages of viral life cycle (attachment, internalization, desencapsidation and formation of viral factories). The four most effective inhibitors (ARV-825, ZL0580, I-BET-762 and PLX51107) were selected for further antiviral activity analysis. These BET/BRD4 inhibitors dose-dependently decreased the ASFV titer, viral RNA transcription and protein production in PAMs. Collectively,our study reported novel activity of BET/BRD4 inhibitors in inducing suppression of ASFV infection, providing insights into role of BET/BRD4 in epigenetic regulation of ASFV and potential new strategies for ASF prevention and control. IMPORTANCESince the continuing spread of the ASFV in the world, and lack of commercial vaccines, the development of improved control strategies including antiviral drugs are urgently needed. BRD4 is an important epigenetic factor and has been commonly used for drug development for tumor treatment. Furthermore, the latest research showed that BET/BRD4 inhibition could suppress replication of virus. In this study, we first showed the inhibitory effect of agents targeting BET/BRD4 on ASFV infection with no significant host cytotoxicity. Then, we found 4 BET/BRD4 inhibitors which can inhibit ASFV replication, RNA transcription and protein synthesis. Finally, we analyzed 4 inhibitors biological effect on BRD4 according to the structure of BRD4, and docking analysis of BET-762, PLX51107, ARV-825 and ZL0580 binding to BD1 and BD2 domains of BRD4 was performed. Our findings support the hypothesis that BET/BRD4 can be considered as attractive host targets in antiviral drug discovery against ASFV.

molecular biology↗

bioRxiv2021

Chemogenetic activation of Locus Coeruleus Noradrenergic Neurons Modulates the Default Mode Network

The default mode network (DMN) of the brain is involved in cognition, emotion regulation, impulsivity, and balancing between internally and externally focused states. DMN dysregulation has been implicated in several neurological and neuropsychiatric disorders. In this study, we used functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and spectral fiber-photometry to investigate the selective neuromodulatory effect of norepinephrine (NE)-releasing noradrenergic neurons in the locus coeruleus (LC) on the DMN in mice. Chemogenetic-induced tonic LC-NE activity decreased cerebral blood volume (CBV) and glucose uptake, and increased synchronous low frequency fMRI activity within the frontal cortices of the DMN. Fiber-photometry results corroborated these findings, showing that LC-NE activation induced NE release, enhanced calcium-weighted neuronal spiking, and reduced CBV in the anterior cingulate cortex. These data suggest that LC-NE alters conventional stimulus-evoked coupling between neuronal activity and CBV in the frontal DMN. We also demonstrated that chemogenetic activation of LC-NE neurons strengthened functional connectivity within the frontal DMN, and this effect was causally mediated by reduced modulatory inputs from retrosplenial and hippocampal regions to the association cortices of the DMN.

neuroscience↗

bioRxiv2021

A Potential Novel COVID-19 Vaccine With RBD-HR1/HR2 Hexamer Structure

The COVID-19 pandemic and the continued spreading of the SARS-CoV-2 variants have brought a grave public health consequence and severely devastated the global economy with recessions. Vaccination is considered as one of the most promising and efficient methods to end the COVID-19 pandemic and mitigate the disease conditions if infected. Although a few vaccines have been developed with an unprecedented speed, scientists around the world are continuing pursuing the best possible vaccines with innovations. Comparing to the expensive mRNA vaccines and attenuated/inactivated SARS-CoV-2 vaccines, recombinant protein vaccines have certain advantages, including their safety (non-virus components), potential stronger immunogenicity, broader protection, ease of scaling-up production, reduced cost, etc. In this study, we reported a novel COVID-19 vaccine generated with RBD-HR1/HR2 hexamer that was creatively fused with the RBD domain and heptad repeat 1 (HR1) or heptad repeat 2 (HR2) to form a dumbbell-shaped hexamer to target the spike S1 subunit. The novel hexamer COVID-19 vaccine induced high titers of neutralizing antibody in mouse studies (>100,000), and further experiments also showed that the vaccine also induced an alternative antibody to the HR1 region, which probably alleviated the drop of immunogenicity from the frequent mutations of SARS-CoV-2.

biochemistry↗

bioRxiv2021

Plasmodium falciparum vacuolar pyrophosphatase 1 for ring stage development and its transition to trophozoite

The malaria parasite relies on anaerobic glycolysis for energy supply when growing inside RBCs as its mitochondrion does not produce ATP. The ring stage lasts [~] 22 hours and is traditionally thought to be metabolically quiescent. However, recent studies show that the ring stage is active for several energy-costly processes including gene transcription/translation, protein export, and movement inside the RBC. It has remained unclear if a low glycolytic flux can meet the energy demand of the ring stage. Here we show that the metabolic by-product, pyrophosphate, is a critical energy source for the development of the ring stage and its transition to the trophozoite stage. During early phases of the asexual development, the parasite utilizes Plasmodium falciparum vacuolar pyrophosphatase 1 (PfVP1), an ancient pyrophosphate-driven proton pump, to pump protons across the parasite plasma membrane to maintain the membrane potential and cytosolic pH. Conditional deletion of PfVP1 leads to delayed ring stage development and a complete blockage of the ring-to-trophozoite transition, which can be partially rescued by Arabidopsis thaliana vacuolar pyrophosphatase 1, but not by the soluble pyrophosphatase from Saccharomyces cerevisiae. Proton-pumping pyrophosphatases are absent in humans, which highlights the possibility of developing highly selective VP1 inhibitors against the malaria parasite.

microbiology↗

bioRxiv2021

End-to-end learning of multiple sequence alignments with differentiable Smith-Waterman

Multiple Sequence Alignments (MSAs) of homologous sequences contain information on structural and functional constraints and their evolutionary histories. Despite their importance for many downstream tasks, such as structure prediction, MSA generation is often treated as a separate pre-processing step, without any guidance from the application it will be used for. Here, we implement a smooth and differentiable version of the Smith-Waterman pairwise alignment algorithm that enables jointly learning an MSA and a downstream machine learning system in an end-to-end fashion. To demonstrate its utility, we introduce SMURF (Smooth Markov Unaligned Random Field), a new method that jointly learns an alignment and the parameters of a Markov Random Field for unsupervised contact prediction. We find that SMURF learns MSAs that mildly improve contact prediction on a diverse set of protein and RNA families. As a proof of concept, we demonstrate that by connecting our differentiable alignment module to AlphaFold and maximizing predicted confidence, we can learn MSAs that improve structure predictions over the initial MSAs. Interestingly, the alignments that improve AlphaFold predictions are self-inconsistent and can be viewed as adversarial. This work highlights the potential of differentiable dynamic programming to improve neural network pipelines that rely on an alignment and the potential dangers of relying on black-box methods for optimizing predictions of protein sequences.

bioinformatics↗

bioRxiv2021

Spatially-resolved transcriptomics analyses of invasive fronts in solid tumors

Solid tumors are complex ecosystems, and heterogeneity is the major challenge for overcoming tumor relapse and metastasis. Uncovering the spatial heterogeneity of cell types and functional states in tumors is essential for developing effective treatment, especially in invasive fronts of tumor, the most active region for tumor cells infiltration and invasion. We firstly used SpaTial Enhanced REsolution Omics-sequencing (Stereo-seq) with a nanoscale resolution to characterize the tumor microenvironment of intrahepatic cholangiocarcinoma (ICC). Enrichment of distinctive immune cells, suppressive immune microenvironment and metabolic reprogramming of tumor cells were identified in the 500{micro}m-wide zone centered bilaterally on the tumor boundary, namely invasive fronts of tumor. Furthermore, we found the damaged states of hepatocytes with overexpression of Serum Amyloid A (SAA) in invasive fronts, recruiting macrophages for facilitating further tumor invasion, and thus resulting in a worse prognosis. We also confirmed these findings in hepatocellular carcinoma and other liver metastatic cancers. Our work highlights the remarkable potential of high-resolution-spatially resolved transcriptomic approaches to provide meaningful biological insights for comprehensively dissecting the tumor ecosystem and guiding the development of novel therapeutic strategies for solid tumors.

cancer biology↗

bioRxiv2021

Immortalization and Functional Screening of Natively Paired Human T Cell Receptor Repertoires

Functional analyses of the T cell receptor (TCR) landscape can reveal critical information about protection from disease and molecular responses to vaccines. However, it has proven difficult to combine advanced next-generation sequencing technologies with methods to decode the peptide-major histocompatibility complex (pMHC) specificity of individual TCRs. Here we developed a new high-throughput approach to enable repertoire-scale functional evaluations of natively paired TCRs. In particular, we leveraged the immortalized nature of physically linked TCR:{beta} amplicon libraries to analyze binding against multiple recombinant pMHCs on a repertoire scale. To exemplify the utility of this approach, we also performed affinity-based functional mapping in conjunction with quantitative next-generation sequencing to track antigen-specific TCRs. These data successfully validated a new immortalization and screening platform to facilitate detailed molecular analyses of human TCRs against diverse antigen targets associated with health, vaccination, or disease.

immunology↗

bioRxiv2021

Outsourced hearing in spiders by using their webs as auditory sensors

Hearing is a fundamental sense of many animals, including all mammals, birds, some reptiles, amphibians, fish, and arthropods. The auditory organs of these animals are extremely diverse in anatomy after hundreds of millions of years of evolution, yet all are made up of cellular tissues and are morphologically part of bodies of animals. Here we show hearing in the orb-weaving spider, Larinioides sclopetarius is not constrained by the organisms body but is extended through outsourcing hearing to its extended phenotype, the proteinaceous, self-manufactured orb-web. We find the wispy, wheel-shaped orb-web acts as a hyperacute acoustic "antenna" to capture the sound-induced air particle movements that approach the maximum physical efficiency, better than the acoustic responsivity of all previously known eardrums. By sensing the motion of web threads, the spider remotely detects and localizes the source of an incoming airborne acoustic wave such as those emitted by approaching prey or predators. By outsourcing its acoustic sensors to its web, the spider is released from body size constraints and permits the araneid spider to increase its sound-sensitive surface area enormously, up to 10,000 times greater than the spider itself. The spider also enables the flexibility to functionally adjust and regularly regenerate its "external eardrum" according to its needs. The "outsourcing" and "supersizing" of auditory function in spiders provides unique features for studying extended and regenerative sensing, and designing novel acoustic flow detectors for precise fluid dynamic measurement and manipulation.

animal behavior and cognition↗

bioRxiv2021

Cnidarian hair cell development illuminates an ancient role for the class IV POU transcription factor in defining mechanoreceptor identity

Although specialized mechanosensory cells are found across animal phylogeny, early evolutionary histories of mechanoreceptor development remain enigmatic. Cnidaria (e.g. sea anemones and jellyfishes) is the sister group to well-studied Bilateria (e.g. flies and vertebrates), and has two mechanosensory cell types - a lineage-specific sensory-effector known as the cnidocyte, and a classical mechanosensory neuron referred to as the hair cell. While developmental genetics of cnidocytes is increasingly understood, genes essential for hair cell development are unknown. Here we show that the class IV POU homeodomain transcription factor (POU-IV) - an indispensable regulator of mechanosensory cell differentiation in Bilateria and cnidocyte differentiation in Cnidaria - controls hair cell development in the sea anemone cnidarian Nematostella vectensis. N. vectensis POU-IV is postmitotically expressed in tentacular hair cells, and is necessary for development of the apical mechanosensory apparatus, but not of neurites, in hair cells. Moreover, it binds to deeply conserved DNA recognition elements, and turns on a unique set of effector genes - including the transmembrane-receptor-encoding gene polycystin 1 - specifically in hair cells. Our results suggest that POU-IV directs differentiation of cnidarian hair cells and cnidocytes via distinct gene regulatory mechanisms, and support an evolutionarily ancient role for POU-IV in defining the mature state of mechanosensory neurons.

evolutionary biology↗

bioRxiv2021

pVHL regulates protein stability of TCF/LEF transcription factor family via ubiquitin-independent proteasomal degradation

The Wnt/{beta}-catenin signaling pathway plays key roles in development and adult tissue homeostasis by controlling cell proliferation and cell fate decisions. In this pathway, transcription factors TCF/LEFs are the key components to repress target gene expression by recruiting co-repressors or to activate target gene expression by recruiting {beta}-catenin when the Wnt signals are absent or present, respectively. While progress has been made in our understanding of Wnt signaling regulation, the underlying mechanism that regulates the protein stability of the TCF/LEF family is far less clear. Here, we show that von Hippel-Lindau protein (pVHL), which is the substrate recognition component in an E3 ubiquitin ligase complex, controls TCF/LEF protein stability. Unexpectedly, pVHL directly binds to TCF/LEFs and promotes their proteasomal degradation independent of E3 ubiquitin ligase activity. Knockout of vhl in zebrafish embryos leads to a reduction of dorsal habenular neurons and this effect is upstream of dorsal habenular neurons phenotype in tcf7l2-null mutants. Our study uncovers a previously unknown mechanism for the protein stability regulation of the TCF/LEF transcription factors and demonstrates that pVHL contains a 26S proteasome binding domain that drives ubiquitin-independent proteasomal degradation. These findings provide new insights into the ubiquitin-independent actions of pVHL and uncover novel mechanistical regulation of Wnt/{beta}-catenin signaling.

cell biology↗

bioRxiv2021

seRNA PAM-1 regulates skeletal muscle satellite cell activation and aging through trans regulation of Timp2 expression synergistically with Ddx5

Muscle satellite cells (SCs) are responsible for muscle homeostasis and regeneration; and lncRNAs play important roles in regulating SC activities. Here in this study, we identify PAM-1 (Pax7 Associated Muscle lncRNA) that is induced in activated SCs to promote SC activation into myoblast cells upon injury. PAM-1 is generated from a myoblast specific super-enhancer (SE); as a seRNA it binds with a number of target genomic loci predominantly in trans. Further studies demonstrate that it interacts with Ddx5 to tether PAM-1 SE to it inter-chromosomal targets Timp2 and Vim to activate the gene expression. Lastly, we show that PAM-1 expression is increased in aging SCs, which leads to enhanced inter-chromosomal interaction and target genes up-regulation. Altogether, our findings identify PAM-1 as a previously unknown lncRNA that regulates both SC activation and aging through its trans gene regulatory activity.

developmental biology↗

bioRxiv2021

High-throughput Activity Assay for Screening Inhibitors of the SARS-CoV-2 Mac1 Macrodomain

Macrodomains are a class of conserved ADP-ribosylhydrolases expressed by viruses of pandemic concern, including coronaviruses and alphaviruses. Viral macrodomains are critical for replication and virus-induced pathogenesis; therefore, these enzymes are a promising target for antiviral therapy. However, no potent or selective viral macrodomain inhibitors currently exist, in part due to the lack of a high-throughput assay for this class of enzymes. Here, we developed a high-throughput ADP-ribosylhydrolase assay using the SARS-CoV-2 macrodomain Mac1. We performed a pilot screen which identified dasatinib and dihydralazine as ADP-ribosylhydrolase inhibitors. Importantly, dasatinib does not inhibit MacroD2, the closest Mac1 homolog in humans. Our study demonstrates the feasibility of identifying selective inhibitors based on ADP-ribosylhydrolase activity, paving the way for screening large compound libraries to identify improved macrodomain inhibitors and explore their potential as antiviral therapies for SARS-CoV-2 and future viral threats.

biochemistry↗