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Protein glycosylation is a common post-translational modification found in all living organisms. This modification in bacterial pathogens plays a pivotal role in their infectious processes including pathogenicity, immune evasion, and host-pathogen interactions. Importantly, many key proteins of host immune systems are also glycosylated and bacterial pathogens can notably modulate glycosylation of these host proteins to facilitate pathogenesis through the induction of abnormal host protein activity and abundance. In recent years, interest in studying the regulation of host protein glycosylation caused by bacterial pathogens is increasing to fully understand bacterial pathogenesis. In this review, we focus on how bacterial pathogens regulate remodeling of host glycoproteins during infections to promote the pathogenesis. [BMB Reports 2021; 54(11): 541-544].

Aim: Both bacterial infection and viral infection involve a large number of protein-protein interactions (PPIs) between a pathogen and its target host. Background: So far, many computational methods have focused on predicting PPIs within the same species rather than PPIs across different species. Methods: From the extensive analysis of PPIs between Yersinia pestis bacteria and humans, we recently discovered an interesting relation; a linear relation between amino acid composition and sequence length was observed in many proteins involved in PPIs. We have built a support vector machine (SVM) model, which predicts PPIs between human and bacteria using two feature types derived from the relation. The two feature types used in the SVM are the amino acid composition group (AACG) and the difference in amino acid composition between host and pathogen proteins. Result: The SVM model achieved high performance in predicting bacteria-human PPIs. The model showed an accuracy of 96%, sensitivity of 94%, and specificity of 98% in predicting PPIs between humans and Yersinia pestis, in which there is a strong relation between amino acid composition and sequence length. The SVM model was also tested in predicting PPIs between human and viruses, which include Ebola, HCV, and SARS-CoV-2, and showed a good performance. Conclusion: The feature types identified in our study are simple yet powerful in predicting pathogenhuman PPIs. Although preliminary, our method will be useful for finding unknown target host proteins or pathogen proteins and designing in vitro or in vivo experiments.

The COVID-19 pandemic has motivated researchers all over the world in trying to find effective drugs and therapeutics for treating this disease. To save time, much effort has focused on repurposing drugs known for treating other diseases than COVID-19. To support these drug repurposing efforts, we built the CAS Biomedical Knowledge Graph and identified 1350 small molecules as potentially repurposable drugs that target host proteins and disease processes involved in COVID-19. A computer algorithm-driven drug-ranking method was developed to prioritize those identified small molecules. The top 50 molecules were analyzed according to their molecular functions and included 11 drugs in clinical trials for treating COVID-19 and new candidates that may be of interest for clinical investigation. The CAS Biomedical Knowledge Graph provides researchers an opportunity to accelerate innovation and streamline the investigative process not just for COVID-19 but also in many other diseases.

Viruses are obligatory intracellular parasites that use cell proteins to take the control of the cell functions in order to accomplish their life cycle. Studying the viral-host interactions would increase our knowledge of the viral biology and mechanisms of pathogenesis. Studies on pathogenesis mechanisms of lyssaviruses, which are the causative agents of rabies, have revealed some important host protein partners for viral proteins, especially for most studied species, i.e. Rabies virus. In this review article, the key physical lyssavirus-host protein interactions, their contributions to rabies infection, and their exploitation are discussed to improve the knowledge about rabies pathogenesis.

The ability of viruses to evolve several orders of magnitude faster than their host cells has enabled them to exploit host cellular machinery by selectively recruiting multiprotein complexes (MPCs) for their catalyzed assembly and replication. This hijacking may depend on alternative, 'moonlighting' functions of host proteins that deviate from their canonical functions thereby inducing cellular pathology. Here, we posit that if virus-induced cellular pathology is similar to that of other, unknown (non-viral) causes, the identification and molecular characterization of the host proteins involved in virus-mediated cellular pathology can be leveraged to decipher the non-viral disease-relevant mechanisms. We focus on how virus-induced aberrant proteostasis and protein aggregation resemble the cellular pathology of sporadic neurodegenerative diseases (NDs) and how this can be exploited for drug discovery.

The lambda (λ) T4rII exclusion (Rex) phenotype is defined as the inability of T4rII to propagate in Escherichia coli lysogenized by bacteriophage λ. The Rex system requires the presence of two lambda immunity genes, rexA and rexB, to exclude T4 (rIIA-rIIB) from plating on a lawn of E. coli λ lysogens. The onset of the Rex phenotype by T4rII infection imparts a harsh cellular environment that prevents T4rII superinfection while killing the majority of the cell population. Since the discovery of this powerful exclusion system in 1955 by Seymour Benzer, few mechanistic models have been proposed to explain the process of Rex activation and the physiological manifestations associated with Rex onset. For the first time, key host proteins have recently been linked to Rex, including σE, σS, TolA, and other membrane proteins. Together with the known Rex system components, the RII proteins of bacteriophage T4 and the Rex proteins from bacteriophage λ, we are closer than ever to solving the mystery that has eluded investigators for over six decades. Here, we review the fundamental Rex components in light of this new knowledge.

To effectively track and eliminate COVID-19, it is critical to develop tools for rapid and accessible diagnosis of actively infected individuals. Here, we introduce a single-walled carbon nanotube (SWCNT)-based optical sensing approach towards these ends. We construct a nanosensor based on SWCNTs noncovalently functionalized with ACE2, a host protein with high binding affinity for the SARS-CoV-2 spike protein. Presence of the SARS-CoV-2 spike protein elicits a robust, two-fold nanosensor fluorescence increase within 90 min of spike protein exposure. We characterize the nanosensor stability and sensing mechanism, and passivate the nanosensor to preserve sensing response in saliva and viral transport medium. We further demonstrate that these ACE2-SWCNT nanosensors retain sensing capacity in a surface-immobilized format, exhibiting a 73% fluorescence turn-on response within 5 s of exposure to 35 mg/L SARS-CoV-2 virus-like particles. Our data demonstrate that ACE2-SWCNT nanosensors can be developed into an optical tool for rapid SARS-CoV-2 detection. ABSTRACT FIGURE

Red blood cells infected with Plasmodium falciparum secrete extracellular vesicles in order to facilitate the survival and infection of human cells. Various researchers have studied the composition of these extracellular vesicles and identified the proteins contained inside. In this work, we used that information to detect potential P. falciparum molecules that could be imitating host proteins. We carried out several searches to detect sequences and structural similarities between the parasite and host. Additionally, the possibility of functional mimicry was explored in line with the potential role that each candidate can perform for the parasite inside the host. Lastly, we determined a set of eight sequences (mainly moonlighting proteins) with a remarkable resemblance to human proteins. Due to the resemblance observed, this study proposes the possibility that certain P. falciparum molecules carried by extracellular vesicles could be imitating human proteins to manipulate the host cell's physiology.

SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design.Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics.Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor–antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

Hepatitis refers to inflammation of the liver and can occur due to a variety of different infectious and non-infectious causes. Viral hepatitis is a well-known example of the disease, and can be caused by a number of viruses. Researchers across the globe are working to shed better light on these viruses. An important discovery in this field was the identification of the receptor for hepatitis B virus (HBV) and hepatitis D virus (HDV) infection and, in 2012, Dr Wenhui Li led a team that reported on important findings regarding sodium taurocholate co-transporting polypeptide (NTCP) as a functional receptor of HBV and HDV. Dr Masashi Iwamoto, National Institute of Infectious Diseases, Japan, is working to further expand knowledge on viral hepatitis infection. He and his team believe that the viral internalization and trafficking processes from plasma membrane could be a potential target for therapeutic solutions. In recent work, Iwamoto demonstrated that the dynamics of viral localization within cells, accompanied by EGFR, is crucial in understanding successful infection. Another element of the team's work is to elucidate the HBV invasion control mechanisms by host protein kinase. In order to do this, the researchers are combining molecular virology with mathematical sciences.

Flaviviruses are a group of important emerging and re-emerging human pathogens that cause worldwide epidemics with thousands of deaths annually. Flaviviruses are small, enveloped, positive-sense, single-stranded RNA viruses that are obligate intracellular pathogens, relying heavily on host cell machinery for productive replication. Proteomic approaches have become an increasingly powerful tool to investigate the mechanisms by which viruses interact with host proteins and manipulate cellular processes to promote infection. Here, we review recent advances in employing quantitative proteomics techniques to improve our understanding of the complex interplay between flaviviruses and host cells. We describe new findings on our understanding of how flaviviruses impact protein-protein interactions, protein-RNA interactions, protein abundance, and post-translational modifications to modulate viral infection.

QL47 a Bruton Tyrosine Kinase inhibitor is a host-targeted, small molecule antiviral that inhibits steady-state viral protein expression. This small molecule broadly inhibits both viral and host protein synthesis and targets a translation step specific to eukaryotic cells and has the potential to be used as an antiviral medication. The aim of the study was to assess the awareness about medical applications of QL-47 among dental students. This was a questionnaire-based cross-sectional type of study comprising 100 dental college students in Chennai. A self-designed questionnaire with ten questions eliciting the knowledge and awareness about QL 47 therapy among dental college students. Questionnaires were circulated through an online website survey planets questions explored the awareness on QL 47 therapy, indications, contraindications, mechanism of action and side effects. After the responses were received from 100 participants, data were collected and analysed.5% were aware about QL 47 therapy. 3% were aware of the mechanism of action of QL 47 therapy. 4% were aware of the indications of QL 47 therapy. 3% were aware of the QL 47 therapy.3%.were aware of the side effects of QL 47 therapy. The awareness about QL 47 in medical applications and managing viral infections was less among dental students. Increased awareness and educational programs should be initiated to spread knowledge about QL 47 therapy.

Increased mortality rates from infectious diseases is a growing public health concern. Successful management of acute bacterial infections requires early diagnosis and treatment, which are not always easy to achieve. Structural imaging techniques such as CT and MRI are often applied to this problem. However, these methods generally rely on secondary inflammatory changes and are frequently not specific to infection. The use of nuclear medicine techniques can add crucial complementary information, allowing visualization of infectious pathophysiology beyond morphologic imaging. This review will discuss the current structural and functional imaging techniques used for the diagnosis of bacterial infection and their roles in different clinical scenarios. We will also present several new radiotracers in development, with an emphasis on probes targeting bacteria-specific metabolism. As highlighted by the current coronavirus disease 2019 epidemic, caused by the novel severe acute respiratory syndrome coronavirus 2, similar thinking may apply in imaging viral pathogens; for this case, prominent effects on host proteins, most notably angiotensin-converting enzyme 2, might also provide worthwhile imaging targets.

As intracellular parasites, viruses co-opt the molecular machinery of the cells they infect in order to multiply and spread, and the extensiveness and effectiveness of this manipulation ultimately determine the outcome of the interaction between virus and host. Members of the Geminiviridae family, causal agents of devastating diseases in crops, encode only a handful of multifunctional, fast-evolving proteins, which efficiently target host proteins to re-wire plant development and physiology and enable replication and spread of the viral genome. In this review, we offer an overview of the different steps in the geminiviral invasion of the host plant, and explore the knowns and unknowns in geminivirus biology.

Transmembrane serine protease 2 (TMPRSS2) has been established as one of the host proteins that facilitate entry of coronaviruses into host cells. One of the approaches often employed towards preventing the entry and proliferation of viruses is computer-aided inhibition studies to identify potent compounds that can inhibit activity of viral targets in the host through binding at the active site. In this study, we developed a pharmacophore model of reportedly potent drugs against severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and -2). The model was used to screen the ZINC database for commercially available compounds having similar features with the experimentally tested drugs. The top 3000 compounds retrieved were docked into the active sites of a homology-modelled TMPRSS2. Docking scores of the top binders were validated and the top-ranked compounds were subjected to ADME, Lipinski’s and medicinal Chemistry property predictions for druglikeness analyses. Two lead compounds, ZINC64606047 and ZINC05296775, were identified having binding affinities higher than those of the reference inhibitors, favorable interactions with TMPRSS2 active site residues and good ADME and medicinal chemistry properties. Molecular dynamics simulation was used to assess the stability and dynamics of the interactions of these compounds with TMPRSS2. Binding free energy and contribution energy evaluations were determined using MMPBSA method. Analyses of the trajectory dynamics collectively established further that the lead compounds bound and interacted stably with active site residues of TMPRSS2. Nonetheless, experimental studies are needed to further assess the potentials of these compounds as possible therapeutics against coronaviruses. Communicated by Ramaswamy H. Sarma.

Free-energy perturbation (FEP) methods are commonly used in drug design to calculate relative binding free energies of different ligands to a common host protein. Alchemical ligand transformations are usually performed in multiple steps which need to be chosen carefully to ensure sufficient phase-space overlap between neighboring states. With one-step or single-step FEP techniques, a single reference state is designed that samples phase-space not only representative of a full transformation but also ideally resembles multiple ligand end states and hence allows for efficient multistate perturbations. Enveloping distribution sampling (EDS) is one example for such a method in which the reference state is created by a mathematical combination of the different ligand end states based on solid statistical mechanics. We have recently proposed a novel approach to EDS which enables efficient barrier crossing between the different end states, termed accelerated EDS (A-EDS). In this work, we further simplify the parametrization of the A-EDS reference state and demonstrate the automated calculation of multiple free-energy differences between different ligands from a single simulation in three different well-described drug design model systems.

Transition metals from manganese to zinc function as catalytic and structural cofactors for an amazing diversity of proteins and enzymes, and thus are essential for all forms of life. During infection, inflammatory host proteins limit the accessibility of multiple transition metals to invading pathogens in a process termed nutritional immunity. In order to respond to host-mediated metal starvation, bacteria employ both protein and RNA-based mechanisms to sense prevailing transition metal concentrations, that collectively regulate systems-level strategies to maintain cellular metallostasis. In this review, we discuss a number of recent advances in our understanding of how bacteria orchestrate the adaptive response to host-mediated multi-metal restriction, highlighting crosstalk among these regulatory systems.

Viruses infect their human hosts by a series of interactions between viral and host proteins, indicating that detailed knowledge of such virus-host interaction interfaces are critical for our understanding of viral infection mechanisms, disease etiology and the development of new drugs. In this review, we primarily survey human host-virus interaction data that are available from public databases following the standardized PSI-MS format. Notably, available host-virus protein interaction information is strongly biased toward a small number of virus families including herpesviridae, papillomaviridae, orthomyxoviridae and retroviridae. While we explore the reliability and relevance of these protein interactions we also survey the current knowledge about viruses functional and topological targets. Furthermore, we assess emerging frontiers of host-virus protein interaction research, focusing on protein interaction interfaces of hosts that are infected by different viruses and viruses that infect multiple hosts. Finally, we cover the current status of research that investigates the relationships of virus-targeted host proteins to other comorbidities as well as the influence of host-virus protein interactions on human metabolism.

Direct‐acting antiviral agents (DAAs) represent a class of drugs targeting viral proteins and have been demonstrated to be very successful in combating viral infections in clinic. However, DAAs suffer from several inherent limitations, including narrow‐spectrum antiviral profiles and liability to drug resistance, and hence there are still unmet needs in the treatment of viral infections. In comparison, host targeting antivirals (HTAs) target host factors for antiviral treatment. Since host proteins are probably broadly required for various viral infections, HTAs are not only perceived, but also demonstrated to exhibit broad‐spectrum antiviral activities. In addition, host proteins are not under the genetic control of viral genome, and hence HTAs possess much higher genetic barrier to drug resistance as compared with DAAs. In recent years, much progress has been made to the development of HTAs with the approval of chemokine receptor type 5 antagonist maraviroc for human immunodeficiency virus treatment and more in the pipeline for other viral infections. In this review, we summarize various host proteins as antiviral targets from a medicinal chemistry prospective. Challenges and issues associated with HTAs are also discussed.

Graphical Abstract Graphical Abstract

From cellular deposition of the HIV-1 capsid to integration of the viral genome, the capsid constitutes a primary target of a variety of host proteins that work to either promote or inhibit HIV-1 infection. Successful progression of HIV-1 infection depends on interactions between the capsid and host factors involved in stability, cellular transport, nuclear import, and genome integration. The virus must also guard its reverse-transcribing genome inside the capsid from host restriction factors that bind the capsid and suppress infection. Understanding the structure and dynamics of the capsid protein (CA) component and the assembled capsid sheds light on the molecular underpinnings of overall capsid stability, architecture, and flexibility that govern HIV-1 capsid–host interactions. The vast majority of these interactions are mediated through recognition of higher order interfaces only present in the assembled capsid lattice. Patterns formed at these interfaces serve as signposts for capsid-binders. Here we provide a graphical summary of the intricate interactions between host factors and the HIV-1 capsid while highlighting recent research. Insights into how host proteins interact with the capsid is crucial for understanding the HIV-1 replication cycle and developing antiviral therapeutics to prevent viral genome integration.

A critical step in studies of the intestinal microbiome using meta-omics approaches is the preservation of samples before analysis. Preservation is essential for approaches that measure gene expression, such as metaproteomics, which is used to identify and quantify proteins in microbiomes. Intestinal microbiome samples are typically stored by flash-freezing and storage at −80°C, but some experimental setups do not allow for immediate freezing of samples. In this study, we evaluated methods to preserve fecal microbiome samples for metaproteomics analyses when flash-freezing is not possible. We collected fecal samples from C57BL/6 mice and stored them for 1 and 4 weeks using the following methods: flash-freezing in liquid nitrogen, immersion in RNAlater, immersion in 95% ethanol, immersion in a RNAlater-like buffer, and combinations of these methods. After storage, we extracted protein and prepared peptides for liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis to identify and quantify peptides and proteins. All samples produced highly similar metaproteomes, except for ethanol-preserved samples that were distinct from all other samples in terms of protein identifications and protein abundance profiles. Flash-freezing and RNAlater (or RNAlater-like treatments) produced metaproteomes that differed only slightly, with less than 0.7% of identified proteins differing in abundance. In contrast, ethanol preservation resulted in an average of 9.5% of the identified proteins differing in abundance between ethanol and the other treatments. Our results suggest that preservation at room temperature in RNAlater or an RNAlater-like solution performs as well as freezing for the preservation of intestinal microbiome samples before metaproteomics analyses. IMPORTANCE Metaproteomics is a powerful tool to study the intestinal microbiome. By identifying and quantifying a large number of microbial, dietary, and host proteins in microbiome samples, metaproteomics provides direct evidence of the activities and functions of microbial community members. A critical step for metaproteomics workflows is preserving samples before analysis because protein profiles are susceptible to fast changes in response to changes in environmental conditions (air exposure, temperature changes, etc.). This study evaluated the effects of different preservation treatments on the metaproteomes of intestinal microbiome samples. In contrast to prior work on preservation of fecal samples for metaproteomics analyses, we ensured that all steps of sample preservation were identical so that all differences could be attributed to the preservation method.

International audience; Originally, viruses were defined as miniscule infectious agents that passed through filters that retain even the smallest cells. Subsequently, viruses were considered obligate intracellular parasites whose reproduction depends on their cellular hosts for energy supply and molecular building blocks. However, these features are insufficient to unambiguously define viruses as they are broadly understood today. We outline possible approaches to define viruses and explore the boundaries of the virosphere within the virtual space of replicators and the relationships between viruses and other types of replicators. Regardless of how, exactly, viruses are defined, viruses clearly have evolved on many occasions from nonviral replicators, such as plasmids, by recruiting host proteins to become virion components. Conversely, other types of replicators have repeatedly evolved from viruses. Thus, the virosphere is a dynamic entity with extensive evolutionary traffic across its boundaries. We argue that the virosphere proper, here termed orthovirosphere, consists of a distinct variety of replicators that encode structural proteins encasing the replicators' genomes, thereby providing protection and facilitating transmission among hosts. Numerous and diverse replicators, such as virus-derived but capsidless RNA and DNA elements, or defective viruses occupy the zone surrounding the orthovirosphere in the virtual replicator space. We define this zone as the perivirosphere. Although intense debates on the nature of certain replicators that adorn the internal and external boundaries of the virosphere will likely continue, we present an operational definition of virus that recently has been accepted by the International Committee on Taxonomy of Viruses.

Introduction The standard TB Four Symptom Screen does not meet the World Health Organization (WHO) ideal screening criteria for having greater than 90% sensitivity to identify active TB disease, regardless of HIV status. To identify novel screening biomarkers for active TB, we performed a systematic review of any cohort or case-control study reporting associations between screening biomarkers and active TB disease. Methods We searched PubMed and Embase for articles published before October 10, 2021. We included studies from high or medium tuberculosis burden countries. We excluded articles focusing on C-reactive protein and lipoarabinomannan. For all included biomarkers, we calculated sensitivity, specificity and 95% confidence intervals, and assessed study quality using a tool adapted from the QUADAS-2 risk of bias. Results From 8,062 abstracts screened, we included 79 articles. The articles described 302 unique biomarkers, including host antibodies, host proteins, TB antigens, microRNAs, whole blood gene PCRs, and combinations of biomarkers. Of these, 23 biomarkers had sensitivity greater than 90% and specificity greater than 70%, meeting WHO criteria for an ideal screening test. Among the eleven biomarkers described in people living with HIV, only one had a sensitivity greater than 90% and specificity greater than 70% for active TB. Conclusion Further evaluation of biomarkers of active TB should be pursued to accelerate identification of TB disease.

Description, HIV spreading relies on a key component of antiviral immunity that tethers nascent virions to the surface of infected cells., BST2 is an interferon-inducible antiviral host protein antagonized by HIV-1 Vpu that entraps nascent HIV-1 virions on the cell surface. Unexpectedly, we find that HIV-1 lacking Nef can revert to full replication competence simply by losing the ability to antagonize BST2. Using gene editing together with cell sorting, we demonstrate that even the propagation of wild-type HIV-1 is strikingly dependent on BST2, including in primary human cells. HIV-1 propagation in BST2−/− populations can be fully rescued by exogenous BST2 irrespective of its capacity to signal and even by an artificial BST2-like protein that shares its virion entrapment activity but lacks sequence homology. Counterintuitively, our results reveal that HIV-1 propagation is critically dependent on basal levels of virion tethering by a key component of innate antiviral immunity.

The metaproteome profiling of cecal contents collected from neonatal piglets fed pasteurized human milk (HM) or a dairy-based infant formula (MF) from postnatal day (PND) 2 to 21 were assessed. At PND 21, a subset of piglets from each group (n = 11/group) were euthanized, and cecal contents were collected for further metaproteome analysis. Cecal microbiota composition showed predominantly more Firmicutes phyla and Lachnospiraceae family in the lumen of cecum of HM-fed piglets in comparison to the MF-fed group. Ruminococcus&nbsp, gnavus was the most abundant species from the Firmicutes phyla in the cecal contents of the HM-fed piglets at 21 days of age. A greater number of expressed proteins were identified in the cecal contents of the HM-fed piglets relative to the MF-fed piglets. Greater abundances of proteins potentially expressed by Bacteroides spp. such as glycoside enzymes were noted in the cecal lumen of HM-fed piglets relative to the MF. Additionally, lyases associated with Lachnospiraceae family were abundant in the cecum of the HM group relative to the MF group. Overall, our findings indicate that neonatal diet impacts the gut bacterial taxa and microbial proteins prior to weaning. The metaproteomics data were deposited into PRIDE, PXD025432 and 10.6019/PXD025432.

MotivationProtein-protein interactions (PPIs) are key elements in numerous biological pathways and the subject of a growing number of drug discovery projects including against infectious diseases. Designing drugs on PPI targets remains a difficult task and requires extensive efforts to qualify a given interaction as an eligible target. To this end, besides the evident need to determine the role of PPIs in disease-associated pathways and their experimental characterization as therapeutics targets, prediction of their capacity to be bound by other protein partners or modulated by future drugs is of primary importance.ResultsWe present InDeep, a tool for predicting functional binding sites within proteins that could either host protein epitopes or future drugs. Leveraging deep learning on a curated data set of PPIs, this tool can proceed to enhanced functional binding site predictions either on experimental structures or along molecular dynamics trajectories. The benchmark of InDeep demonstrates that our tool outperforms state of the art ligandable binding sites predictors when assessing PPI targets but also conventional targets. This offers new opportunities to assist drug design projects on PPIs by identifying pertinent binding pockets at or in the vicinity of PPI interfaces.AvailabilityThe tool is available on GitHub3 along with a PyMol plugin for visualization. Predictions of InDeep can be consulted at iPPI-DB4

The emergence of pandemic situations originated from SARS-CoV-2 and its new variants created worldwide medical emergencies. Due to the non-availability of efficient drugs and vaccines, hundreds of thousands of people succumbed to death intoxicated by this virus. At these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS-CoV-2. Using a high-throughput screening approach, we validated a list of potential repurposed drugs, like Nafamostat, Camostat, Silmitasertib, Valproic acid, Zotatifin, and essential host target proteins HDAC2, eIF4E2, CSK22, that are essential for viral mechanism. We determined multiple dissociation pathways of repurposed drugs, suggesting the availability of sub pockets within the host target proteins. We showed the preferential residues involved in the (un)binding kinetics of the ligands correlated to the underlying mechanism of the host protein activity. Interestingly, the residues we obtained for HDAC2 and CSK22 target proteins, which we highlighted, are also involved in the catalytic activity. The mechanistic insight presented in this work is envisaged to help use these key host proteins and potential repurposed drugs as a treatment for the SARS-CoV-2 virus.

Despite the continuous discovery of host and guest proteins in membraneless organelles, complex host–guest interactions hinder the understanding of the molecular grammar governing liquid–liquid phase separation. In this study, we characterized the localization and dynamic properties of guest proteins in liquid droplets using single-molecule fluorescence microscopy. Eighteen guest proteins of different sizes, structures, and oligomeric states were examined in host p53 liquid droplets. Recruitment did not significantly depend on the structural properties of the guest proteins, but was moderately correlated with their length, total charge, and number of R and Y residues. In contrast, the diffusion of disordered guest proteins was comparable to that of host p53, whereas that of folded proteins varied widely. Molecular dynamics simulations suggest that folded proteins diffuse within the voids of the liquid droplet while interacting weakly with neighboring host proteins, whereas disordered proteins adapt their structures to form tight interactions with the host proteins. Our study provides insights into the key molecular principles of the localization and dynamics of guest proteins in liquid droplets.

The coronavirus disease 2019 (COVID‐19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), is threatening people's lives and impacting their health. It is still unclear whether people engaged in physical activity are at an increased risk of SARS‐CoV‐2 infection and severe forms of COVID‐19. In order to provide data to help answer this question, we, therefore, investigated the effects of endurance training on the levels of host proteins involved in SARS‐CoV‐2 infection in mice. Eight‐week‐old C57BL/6J mice were subjected to treadmill running (17–25 m/min, 60–90 min, 5 sessions/week, 8 weeks). After the intervention, the levels of angiotensin‐converting enzyme 2 (ACE2; host receptor for SARS‐CoV‐2), transmembrane protease serine 2 (TMPRSS2; host protease priming fusion of SARS‐CoV‐2 to host cell membranes), FURIN (host protease that promotes binding of SARS‐CoV‐2 to host receptors), and Neuropilin‐1 (host coreceptor for SARS‐CoV‐2) were measured in 10 organs that SARS‐CoV‐2 can infect (larynx, trachea, lung, heart, jejunum, ileum, colon, liver, kidney, and testis). Six organs (heart, lung, jejunum, liver, trachea, and ileum) showed changes in the levels of at least one of the proteins. Endurance training increased ACE2 levels in heart (+66.4%), lung (+37.1%), jejunum (+24.7%) and liver (+27.4%), and FURIN in liver (+17.9%) tissue. In contrast, endurance training decreased Neuropilin‐1 levels in liver (−39.7%), trachea (−41.2%), and ileum (−39.7%), and TMPRSS2 in lung (−11.3%). Taken together, endurance training altered the levels of host proteins involved in SARS‐CoV‐2 cell entry in an organ‐dependent manner.

This is the accepted manuscript version of the work published in its final form as McCowin, Sayo;Marie, Chelsea;Petri, William A. Trends in Parasitology; Volume: 37; Issue: 11; Pages: 937–939; https://doi.org/10.1016/j.pt.2021.09.004 Deposited byshareyourpaper.organdopenaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailinghelp@openaccessbutton.org.