Am J Med Sci. 2021 Feb 25:S0002-9629(21)00072-0. doi: 10.1016/j.amjms.2021.02.019. Online ahead of print.

ABSTRACT

Coronaviruses disease 2019 (COVID-19) is the most crucial threat, the world has ever witnessed. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of this disease pandemic. The World Health Organization has confirmed the continuing epidemic as a worldwide public health crisis. Presently, the research on COVID-19 is even in the primitive stage. Studies on unveiling the natural route of COVID-19 infection and related pathophysiology, the biology of pulmonary airways pose a more rational restorative approach in the management of COVID-19. Thus, based on the existing facts, we methodically reviewed the efforts put forth by various research institutes, pharmaceutical companies and biotechnology firms in pulmonary delivery to prevent and control the COVID-19. This article would be valuable for the healthcare community, which is efficiently dealing with the SARS-CoV-2 crisis.

PMID:33640363 | DOI:10.1016/j.amjms.2021.02.019

Epilepsia. 2021 Feb 27. doi: 10.1111/epi.16849. Online ahead of print.

ABSTRACT

Developmental and epileptic encephalopathies (DEEs) are among the most challenging of all epilepsies to manage, given the exceedingly frequent and often severe seizure types, pharmacoresistance to conventional antiseizure medications, and numerous comorbidities. During the past decade, efforts have focused on development of new treatment options for DEEs, with several recently approved in the United States or Europe, including cannabidiol as an orphan drug in Dravet and Lennox-Gastaut syndromes and everolimus as a possible antiepileptogenic and precision drug for tuberous sclerosis complex, with its impact on the mammalian target of rapamycin pathway. Furthermore, fenfluramine, an old drug, was repurposed as a novel therapy in the treatment of Dravet syndrome. The evolution of new insights into pathophysiological processes of various DEEs provides possibilities to investigate novel and repurposed drugs and to place them into the context of their role in future management of these patients. The purpose of this review is to provide an overview of these new medical treatment options for the DEEs and to discuss the clinical implications of these results for improved treatment.

PMID:33638459 | DOI:10.1111/epi.16849

Bioinformatics. 2021 Feb 26:btab130. doi: 10.1093/bioinformatics/btab130. Online ahead of print.

ABSTRACT

MOTIVATION: A global effort is underway to identify compounds for the treatment of COVID-19. Since de novo compound design is an extremely long, time-consuming, and expensive process, efforts are underway to discover existing compounds that can be repurposed for COVID-19 and new viral diseases.

MODEL: We propose a machine learning representation framework that uses deep learning induced vector embeddings of compounds and viral proteins as features to predict compound-viral protein activity. The prediction model in-turn uses a consensus framework to rank approved compounds against viral proteins of interest.

RESULTS: Our consensus framework achieves a highmean Pearson correlation of 0.916, mean R2 of 0.840 and a low mean squared error of 0.313 for the task of compound-viral protein activity prediction on an independent test set. As a use case, we identify a ranked list of 47 compounds common to three main proteins of SARS-COV-2 virus (PL-PRO, 3CL-PRO and Spike protein) as potential targets including 21 antivirals, 15 anticancer, 5 antibiotics and 6 other investigationalhuman compounds.We performadditional molecular docking simulations to demonstrate thatmajority of these compounds have low binding energies and thus high binding affinity with the potential to be effective against the SARS-COV-2 virus.

AVAILABILITY: All the source code and data is available at: https://github.com/raghvendra5688/Drug-Repurposing and https://dx.doi.org/10.17632/8rrwnbcgmx.3. We also implemented a web-server at: https://machinelearning-protein.qcri.org/index.html.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:33638345 | DOI:10.1093/bioinformatics/btab130

Sci Data. 2021 Feb 26;8(1):70. doi: 10.1038/s41597-021-00848-4.

ABSTRACT

SARS-CoV-2 is a novel coronavirus responsible for the COVID-19 pandemic, in which acute respiratory infections are associated with high socio-economic burden. We applied high-content screening to a well-defined collection of 5632 compounds including 3488 that have undergone previous clinical investigations across 600 indications. The compounds were screened by microscopy for their ability to inhibit SARS-CoV-2 cytopathicity in the human epithelial colorectal adenocarcinoma cell line, Caco-2. The primary screen identified 258 hits that inhibited cytopathicity by more than 75%, most of which were not previously known to be active against SARS-CoV-2 in vitro. These compounds were tested in an eight-point dose response screen using the same image-based cytopathicity readout. For the 67 most active molecules, cytotoxicity data were generated to confirm activity against SARS-CoV-2. We verified the ability of known inhibitors camostat, nafamostat, lopinavir, mefloquine, papaverine and cetylpyridinium to reduce the cytopathic effects of SARS-CoV-2, providing confidence in the validity of the assay. The high-content screening data are suitable for reanalysis across numerous drug classes and indications and may yield additional insights into SARS-CoV-2 mechanisms and potential therapeutic strategies.

PMID:33637768 | DOI:10.1038/s41597-021-00848-4

Mol Pharmacol. 2021 Feb 25:MOLPHARM-AR-2020-000210. doi: 10.1124/molpharm.120.000210. Online ahead of print.

ABSTRACT

Celecoxib is one of the most common medicines for treating inflammatory diseases. Recently, it has been shown that celecoxib is associated with implications in complex diseases such as Alzheimer's disease and cancer, as well as with cardiovascular risk assessment and toxicity, suggesting that celecoxib may affect multiple unknown targets. In this project, we detected targets of celecoxib within the nervous system using a label-free TPP (Thermal Proteome Profiling) method. First, proteins of the rat hippocampus were treated with multiple drug concentrations and temperatures. Next, we separated the soluble proteins from the denatured and sedimented total protein load by ultracentrifugation. Subsequently, the soluble proteins were analyzed by nano-liquid chromatography-mass spectrometry to determine the identity of the celecoxib targeted proteins based on structural changes by thermal stability variation of targeted proteins towards higher solubility in the higher temperatures. In the analysis of the soluble protein extract at 67 centigrade, 44 proteins were uniquely detected in drug-treated samples out of all 478 identified proteins at this temperature. Rab4a, one out of these 44 proteins, has previously been reported as one of the celecoxib off-targets in the rat CNS. Furthermore, we provide more molecular details through biomedical enrichment analysis to explore the potential role of all detected proteins in the biological systems. We show that the determined proteins play a role in the signaling pathways related to neurodegenerative disease - and cancer pathways. Finally, we fill out molecular supporting evidence for using celecoxib towards the drug repurposing approach by exploring drug targets. Significance Statement In this study, we determined forty-four off-target proteins of celecoxib, a non-steroidal anti-inflammatory, and one of the most common medicines for treating inflammatory diseases. We showed that these proteins play a role in the signaling pathways related to neurodegenerative disease and cancer pathways. Finally, we provided molecular supporting evidence for using celecoxib towards the drug repurposing approach by exploring drug targets.

PMID:33632781 | DOI:10.1124/molpharm.120.000210

Mini Rev Med Chem. 2021 Feb 24. doi: 10.2174/1389557521666210225114733. Online ahead of print.

ABSTRACT

COVID-19 disease, caused by the SARS CoV-2 virus, has been announced as Pandemic by the WHO. To date it has affected almost every part of the world, more than 39.8 million people were infected and up to 1.11 million have lost their lives. Currently, there has been no success to develop measures to cure the disease. Additionally, the vaccine development may take several months, and many novel drug molecules attempted have been fallen short of achieving success yet. Hence, an effective alternative solution is a need for these darkest hours. Repurposing of drugs has already proved efficacy in diseases, like, and it significantly provides the most acceptable alternative. There are hundreds of drug molecules approved for clinical trials by the FDA. SARS COV 2 virus has shown resemblance with enzyme targets such as 3CLpro/Mpro, RdRp, Cathepsin L, and TMPRSS2 with SARS CoV and MERS CoV that gives an option to use drugs that have shown efficacy in these viruses for COVID-19 (Corona Virus Disease) treatment. This review focuses on why repurposing could provide a better alternative in COVID-19 treatment and the similarity in the structural and progression of infection of these viruses gives a direction and validation to evaluate the drugs approved for SARS and MERS against COVID-19. It has been indicated that multiple therapeutic options that demonstrate efficacy against SARS CoV 2 are available to mitigate the potential emergence of COVID-19 infection.

PMID:33632095 | DOI:10.2174/1389557521666210225114733

Adv Exp Med Biol. 2021 Feb 25. doi: 10.1007/5584_2021_622. Online ahead of print.

ABSTRACT

One of the critical Global challenges in achieving the UN Sustainable Development Goals 3 Good Health and Well Being is optimizing drug discovery and translational research for unmet medical need in both communicable and non-communicable diseases. Recently, the WHO reports there has been a shift from communicable diseases to non-communicable diseases with respect to being the leading cause of death globally and particularly in low- and middle-income countries such as South Africa. Hence, there is current drive to establish functional precision medicine program that addresses the unmet medical need using high throughput drug sensitivity and drug repurposing platform. Here, this paper serves as a perspective to showcase the recent development in high throughput drug sensitivity screening platform for the cancer precision medicine. We also elaborate on the benefit and applications of high-throughput drug screening platform for Precision Medicine. From a future perspective, this paper aims to showcase the possibility to integrate existing high-throughput drug sensitivity screening platform with the newly developed platform technologies such as microfluidics based single cell drug screening.

PMID:33629259 | DOI:10.1007/5584_2021_622

Biomed Res Int. 2021 Feb 10;2021:6690154. doi: 10.1155/2021/6690154. eCollection 2021.

ABSTRACT

The prediction of drug-target interaction (DTI) is a key step in drug repositioning. In recent years, many studies have tried to use matrix factorization to predict DTI, but they only use known DTIs and ignore the features of drug and target expression profiles, resulting in limited prediction performance. In this study, we propose a new DTI prediction model named AdvB-DTI. Within this model, the features of drug and target expression profiles are associated with Adversarial Bayesian Personalized Ranking through matrix factorization. Firstly, according to the known drug-target relationships, a set of ternary partial order relationships is generated. Next, these partial order relationships are used to train the latent factor matrix of drugs and targets using the Adversarial Bayesian Personalized Ranking method, and the matrix factorization is improved by the features of drug and target expression profiles. Finally, the scores of drug-target pairs are achieved by the inner product of latent factors, and the DTI prediction is performed based on the score ranking. The proposed model effectively takes advantage of the idea of learning to rank to overcome the problem of data sparsity, and perturbation factors are introduced to make the model more robust. Experimental results show that our model could achieve a better DTI prediction performance.

PMID:33628808 | PMC:PMC7889346 | DOI:10.1155/2021/6690154

Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2016265118. doi: 10.1073/pnas.2016265118.

ABSTRACT

Previous studies have demonstrated that the synaptic EphB1 receptor tyrosine kinase is a major mediator of neuropathic pain, suggesting that targeting the activity of this receptor might be a viable therapeutic option. Therefore, we set out to determine if any FDA-approved drugs can act as inhibitors of the EphB1 intracellular catalytic domain. An in silico screen was first used to identify a number of tetracycline antibiotics which demonstrated potential docking to the ATP-binding catalytic domain of EphB1. Kinase assays showed that demeclocycline, chlortetracycline, and minocycline inhibit EphB1 kinase activity at low micromolar concentrations. In addition, we cocrystallized chlortetracycline and EphB1 receptor, which confirmed its binding to the ATP-binding domain. Finally, in vivo administration of the three-tetracycline combination inhibited the phosphorylation of EphB1 in the brain, spinal cord, and dorsal root ganglion (DRG) and effectively blocked neuropathic pain in mice. These results indicate that demeclocycline, chlortetracycline, and minocycline can be repurposed for treatment of neuropathic pain and potentially for other indications that would benefit from inhibition of EphB1 receptor kinase activity.

PMID:33627480 | DOI:10.1073/pnas.2016265118

Genome Res. 2021 Feb 24:gr.272484.120. doi: 10.1101/gr.272484.120. Online ahead of print.

ABSTRACT

Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA in order to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metabolite-enzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched by neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1). We identify shared immune pathways between DAM and DAA, including Th17 cell differentiation and chemokine signaling. Lastly, integrative metabolite-enzyme network analyses suggest that fatty acids and amino acids may trigger molecular alterations in DAM and DAA. Combining network-based prediction and retrospective case-control observations with 7.2 million individuals, we identify that usage of fluticasone (an approved glucocorticoid receptor agonist) is significantly associated with a reduced incidence of AD (hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.83-0.89, p<1.0×10-8). Propensity score-stratified cohort studies reveal that usage of mometasone (a stronger glucocorticoid receptor agonist) is significantly associated with a decreased risk of AD (HR=0.74, 95% CI 0.68-0.81, p<1.0×10-8) compared to fluticasone after adjusting age, gender, and disease comorbidities. In summary, we present a network-based, multimodal methodology for single-cell/nucleus genomics-informed drug discovery and has identified fluticasone and mometasone as potential treatments in AD.

PMID:33627474 | DOI:10.1101/gr.272484.120

Circ Genom Precis Med. 2021 Feb 24. doi: 10.1161/CIRCGEN.120.003196. Online ahead of print.

ABSTRACT

Background - Randomized clinical trials indicate that the immune response plays a significant role in coronary artery disease (CAD), a disorder impacting the lifespan potential. However, the identification of targets critical to the immune response in atheroma is still hampered by a lack of solid inference. Methods - Herein, we implemented a system genetics approach to identify causally associated immune targets implicated in atheroma. We leveraged genome-wide association studies to perform mapping and Mendelian Randomization (MR) to assess causal associations between gene expression in blood cells with CAD and the lifespan. Expressed genes (eGenes) were prioritized in network and in single-cell expression derived from plaque immune cells. Results - Among 840 CAD-associated blood eGenes, 37 were predicted causally associated with CAD and 6 were also associated with the parental lifespan in MR. In multivariable MR, the impact of eGenes on the lifespan potential was mediated by the CAD risk. Predicted causal eGenes were central in network. FLT1 and CCR5 were identified as targets of approved drugs, whereas 22 eGenes were deemed tractable for the development of small molecules and/or antibodies. Analyses of plaque immune single-cell expression identified predicted causal eGenes enriched in macrophages (GPX1, C4orf3) and involved in ligand receptor interactions (CCR5). Conclusions - We identified 37 blood eGenes predicted causally associated with CAD. The predicted expression for 6 eGenes impacted the lifespan potential through the risk of CAD. Prioritization based on network, annotations and single cell expression identified targets deemed tractable for the development of drugs and for drug repurposing.

PMID:33625251 | DOI:10.1161/CIRCGEN.120.003196

Biosci Rep. 2021 Feb 24:BSR20202616. doi: 10.1042/BSR20202616. Online ahead of print.

ABSTRACT

Since the emergence of the new severe acute respiratory syndrome-related coronaviruses 2 (SARS-CoV-2) at the end of December 2019 in China, and with the urge of the coronavirus disease 2019 (COVID-19) pandemic, there have been a huge effort of many research teams and governmental institutions worldwide to mitigate the current scenario. Reaching more than 1,377,000 deaths in the world and still with a growing number of infections, SARS-CoV-2 remains a critical issue for global health and economic systems, with an urgency for available therapeutic options. In this scenario, as drug repurposing and discovery remains a challenge, computer-aided drug design (CADD) approaches, including machine learning (ML) techniques, can be useful tools to the design and discovery of novel potential antiviral inhibitors against SARS-CoV-2. In this work, we describe and review the current knowledge on this virus and the pandemic, the latest strategies and computational approaches applied to search for treatment options, as well as the challenges to overcome COVID-19.

PMID:33624754 | DOI:10.1042/BSR20202616

JAMIA Open. 2020 Dec 31;3(4):536-544. doi: 10.1093/jamiaopen/ooaa048. eCollection 2020 Dec.

ABSTRACT

OBJECTIVE: Observational medical databases, such as electronic health records and insurance claims, track the healthcare trajectory of millions of individuals. These databases provide real-world longitudinal information on large cohorts of patients and their medication prescription history. We present an easy-to-customize framework that systematically analyzes such databases to identify new indications for on-market prescription drugs.

MATERIALS AND METHODS: Our framework provides an interface for defining study design parameters and extracting patient cohorts, disease-related outcomes, and potential confounders in observational databases. It then applies causal inference methodology to emulate hundreds of randomized controlled trials (RCTs) for prescribed drugs, while adjusting for confounding and selection biases. After correcting for multiple testing, it outputs the estimated effects and their statistical significance in each database.

RESULTS: We demonstrate the utility of the framework in a case study of Parkinson's disease (PD) and evaluate the effect of 259 drugs on various PD progression measures in two observational medical databases, covering more than 150 million patients. The results of these emulated trials reveal remarkable agreement between the two databases for the most promising candidates.

DISCUSSION: Estimating drug effects from observational data is challenging due to data biases and noise. To tackle this challenge, we integrate causal inference methodology with domain knowledge and compare the estimated effects in two separate databases.

CONCLUSION: Our framework enables systematic search for drug repurposing candidates by emulating RCTs using observational data. The high level of agreement between separate databases strongly supports the identified effects.

PMID:33623890 | PMC:PMC7886555 | DOI:10.1093/jamiaopen/ooaa048

Inform Med Unlocked. 2021 Feb 19:100539. doi: 10.1016/j.imu.2021.100539. Online ahead of print.

ABSTRACT

In 2020 SARS-CoV-2 reached pandemic status, reaching Brazil in mid-February. As of now, no specific drugs for treating the disease are available. In this work, the possibility of interaction between SARS-CoV-2 viral proteins (open and closed spike protein, isolate spike protein RBD, NSP 10, NSP 16, main protease, and RdRp polymerase) and multiple molecules is addressed through the repositioning of drugs available for the treatment of other diseases that are approved by the FDA and covered by SUS, the Brazilian Public Health System. Three different docking software were used, followed by a unification of the results by independent evaluation. Afterwards, the chemical interactions of the compounds with the targets were inspected via molecular dynamics and analyzed. The results point to a potential effectiveness of Penciclovir, Ribavirin, and Zanamivir, from a set of 48 potential candidates. They may also be multi-target drugs, showing high affinity with more than one viral protein. Further in vitro and in vivo validation is required to assess the suitability of repositioning the proposed drugs for COVID-19.

PMID:33623816 | PMC:PMC7893290 | DOI:10.1016/j.imu.2021.100539

J Agric Food Chem. 2021 Feb 23. doi: 10.1021/acs.jafc.0c06755. Online ahead of print.

ABSTRACT

Screening potential compounds for improving ulcerative colitis (UC) from clinical medication is an effective strategy for drug repurposing. We applied bioinformatics and network pharmacology to the drug screening process in this study, which helped us to screen out troxerutin that could improve UC. Troxerutin belongs to flavonoids and is used clinically as an anticoagulant and thrombolytic agent. This study found a new pharmacological activity of troxerutin, that is, it had a significant improvement effect on UC in mice. Experimental results of in vitro and in vivo levels showed that troxerutin could effectively reduce the level of oxidative stress that caused damages in intestinal epithelial cells and colonic tissue, maintain the distribution and expression of tight junction-related proteins, and protect the barrier function of colon tissue. In addition to the oxidative stress, severe inflammatory response is also an important pathological factor that aggravates UC. However, troxerutin could reduce the infiltration of inflammatory cells in the colon tissue and decrease the expression of inflammation-related proteins and proinflammatory cytokines. Due to its antioxidant and anti-inflammatory effects, troxerutin inhibited the process of cell apoptosis in the colon tissue and relieved the degree of colonic fibrosis. Bioinformatics analysis showed that the ameliorating effect of troxerutin on UC was probably related to its network regulation of signaling pathways. In summary, we discovered a new pharmacological activity of the flavonoid troxerutin against UC, which is conducive to the expansion and application of flavonoids in the treatment of human diseases.

PMID:33621077 | DOI:10.1021/acs.jafc.0c06755

Antimicrob Agents Chemother. 2021 Feb 22:AAC.02676-20. doi: 10.1128/AAC.02676-20. Online ahead of print.

ABSTRACT

Drug combination therapy is an interesting approach to increase the success of drug repurposing for neglected diseases. Thus, the objective of this work was to evaluate binary and ternary therapies composed of itraconazole, ezetimibe and miltefosine for the treatment of visceral leishmaniasis. Intracellular Leishmania infantum amastigotes were incubated with the drugs alone or in combination for 72 h. For in vivo experiments, we tested a long-course (21 days, once per day) and a short-course treatment (5 days, twice per day) for the binary combination with itraconazole and ezetimibe. For the ternary therapy including miltefosine, we adopted the short-course treatment and varied the vehicle. None of the combinations were toxic to macrophages. Binary combination of itraconazole plus ezetimibe and ternary combination of itraconazole, ezetimibe and miltefosine had synergistic effects in intracellular amastigotes, in some of the proportions evaluated. Although the in vivo long-course therapy had been more effective than the short-course protocol, it showed hepatic toxicity signs. Ezetimibe has proven to be able to reduce the parasite burden alone or in combination. Both suspensions of the ternary combination were active, but when the drugs were suspended in the commercial ORA-Plus formulation instead of purified water, the parasite burden was reduced by 98% in the liver and spleen. Altogether, the results demonstrate for the first time the activity of ezetimibe in a viscerotropic species of Leishmania and indicate that ternary treatment composed of miltefosine, itraconazole, and ezetimibe at low doses is a promising therapeutic alternative for the treatment of visceral leishmaniasis.

PMID:33619058 | DOI:10.1128/AAC.02676-20

Trends Microbiol. 2021 Feb 19:S0966-842X(21)00016-0. doi: 10.1016/j.tim.2021.01.014. Online ahead of print.

ABSTRACT

Besides its prominent role in cell proliferation, cyclin-dependent kinases (CDKs) are key players in viral infections as both DNA and RNA viruses modify CDK function to favor viral replication. Recently, a number of specific pharmacological CDK inhibitors have been developed and approved for cancer treatment. The repurposing of these specific CDK inhibitors for the treatment of viral infections may represent a novel effective therapeutic strategy to combat old and emergent viruses. In this review, we describe the role, mechanisms of action, and potential of CDKs as antiviral drug targets. We also discuss the current clinical state of novel specific CDK inhibitors, focusing on their putative use as antivirals, especially against new emerging viruses.

PMID:33618979 | DOI:10.1016/j.tim.2021.01.014

Eur J Pharm Sci. 2021 Feb 19:105771. doi: 10.1016/j.ejps.2021.105771. Online ahead of print.

ABSTRACT

AIMS: Cell surface binding immunoglobin protein (csBiP) is predicted to be susceptible to SARS-CoV-2 binding. With a substrate-binding domain (SBD) that binds to polypeptides and a nucleotide-binding domain (NBD) that can initiate extrinsic caspase-dependent apoptosis, csBiP may be a promising therapeutic target for COVID-19. This study aims to identify FDA-approved drugs that can neutralize viral binding and prevent viral replication by targeting the functional domains of csBiP.

METHODS: In silico screening of 1999 FDA-approved drugs against the functional domains of BiP were performed using three molecular docking programs to avoid bias from individual docking programs. Top ligands were selected by averaging the ligand rankings from three programs. Interactions between top ligands and functional domains of BiP were analyzed.

KEY FINDINGS: The top 10 SBD-binding candidates are velpatasvir, irinotecan, netupitant, lapatinib, doramectin, conivaptan, fenoverine, duvelisib, irbesartan, and pazopanib. The top 10 NBD-binding candidates are nilotinib, eltrombopag, grapiprant, topotecan, acetohexamide, vemurafenib, paritaprevir, pixantrone, azosemide, and piperaquine-phosphate. Among them, Velpatasvir and paritaprevir are antiviral agents that target the protease of hepatitis C virus. Netupitant is an anti-inflammatory drug that inhibits neurokinin-1 receptor, which contributes to acute inflammation. Grapiprant is an anti-inflammatory drug that inhibits the prostaglandin E2 receptor protein subtype 4, which is expressed on immune cells and triggers inflammation. These predicted SBD-binding drugs could disrupt SARS-CoV-2 binding to csBiP, and NBD-binding drugs may falter viral attachment and replication by locking the SBD in closed conformation and triggering apoptosis in infected cells.

SIGNIFICANCE: csBiP appears to be a novel therapeutic target against COVID-19 by preventing viral attachment and replication. These identified drugs could be repurposed to treat COVID-19 patients.

PMID:33617948 | DOI:10.1016/j.ejps.2021.105771

J Natl Black Nurses Assoc. 2020 Dec;31(2):1-14.

ABSTRACT

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and associated coronavirus disease 19 (COVID-19) began ravaging most of the globe in November 2019. In the United States more than 25 million people have been infected with SARS-CoV-2. To date, COVID-19 has killed close to 400,000 U.S. citizens. In the face of limited pharmacotherapies, the current burden of SARS-CoV-2 and COVID-19 signals overwhelming sickness and trillions in healthcare costs ahead. The need to expeditiously identify safe and efficacious prophylaxis and treatment options is critical. Drug repositioning may be a promising strategy toward mitigating the impact of SARS-CoV-2 and COVID-19. This rapid review appraises available evidence on the viability of vintage antimalarial drugs chloroquine (CHQ) and its analog hydroxychloroquine (HCQ) repositioned for SARS-CoV-2 prophylaxis and COVID-19 treatment. Findings suggest neither the use of CHQ nor HCQ singularly, or concomitantly, with azithromycin and/or zinc provide definitive benefits for use against SARS-CoV-2 infection or COVID-19 illness. Moreover, administration of these medications was linked to significant and sometimes fatal complications.

PMID:33617702

Expert Opin Pharmacother. 2021 Feb 22. doi: 10.1080/14656566.2021.1892641. Online ahead of print.

ABSTRACT

Introduction: Compared to other medical disorders, including other brain diseases, the number of medications approved for AUD is small and they generally have limited efficacy, which is due to several factors including the wide heterogeneity of patients with AUD. Areas covered: In this review, the authors aim to synthesise literature for new approved and emerging pharmacotherapies for AUD. Recently approved medications include nalmefene, which was approved in Europe and Australia for the purposes of controlled drinking. Baclofen has also been approved in France but not in other countries. Off label medications including topiramate and gabapentin have received significant attention with multiple RCTs and meta-analyses and have widespread use in several countries including the USA. Several novel medications have emerged over the last decade but further work is required to determine their efficacy and safety for the widespread management of AUD. Expert opinion: Despite significant advances in our understanding of the neurobiological basis of factors that contribute to the development and maintenance of AUD, there have been few new AUD medications approved for almost 20 years. There are many challenges to the development and intoduction of new pharmacotherapies for AUD. Strategies for improving the translational pipeline include drug repurposing and utilisation of human acute laboratory models.

PMID:33615945 | DOI:10.1080/14656566.2021.1892641