Appl Microbiol Biotechnol. 2021 Jun 21. doi: 10.1007/s00253-021-11407-7. Online ahead of print.

ABSTRACT

The morbidity and mortality caused by invasive fungal infections are increasing across the globe due to developments in transplant surgery, the use of immunosuppressive agents, and the emergence of drug-resistant fungal strains, which has led to a challenge in terms of treatment due to the limitations of three classes of drugs. Hence, it is imperative to establish effective strategies to identify and design new antifungal drugs. Drug repurposing is a potential way of expanding the application of existing drugs. Recently, various existing drugs have been shown to be useful in the prevention and treatment of invasive fungi. In this review, we summarize the currently used antifungal agents. In addition, the most up-to-date information on the effectiveness of existing drugs with antifungal activity is discussed. Moreover, the antifungal mechanisms of existing drugs are highlighted. These data will provide valuable knowledge to stimulate further investigation and clinical application in this field. KEY POINTS: • Conventional antifungal agents have limitations due to the occurrence of drug-resistant strains. • Non-antifungal drugs act as antifungal agents in various ways toward different targets. • Non-antifungal drugs with antifungal activity are demonstrated as effective antifungal strategies.

PMID:34151414 | DOI:10.1007/s00253-021-11407-7

Front Pharmacol. 2021 Jun 4;12:695009. doi: 10.3389/fphar.2021.695009. eCollection 2021.

ABSTRACT

Endothelial barrier integrity is important for vascular homeostasis, and hyperpermeability participates in the progression of many pathological states, such as diabetic retinopathy, ischemic stroke, chronic bowel disease, and inflammatory disease. Here, using drug repositioning, we discovered that primaquine diphosphate (PD), previously known as an antimalarial drug, was a potential blocker of vascular leakage. PD inhibited the linear pattern of vascular endothelial growth factors (VEGF)-induced disruption at the cell boundaries, blocked the formation of VEGF-induced actin stress fibers, and stabilized the cortactin actin rings in endothelial cells. PD significantly reduced leakage in the Miles assay and mouse model of streptozotocin (STZ)-induced diabetic retinopathy. Targeted prediction programs and deubiquitinating enzyme activity assays identified a potential mechanism of action for PD and demonstrated that this operates via ubiquitin specific protease 1 (USP1). USP1 inhibition demonstrated a conserved barrier function by inhibiting VEGF-induced leakage in endothelial permeability assays. Taken together, these findings suggest that PD could be used as a novel drug for vascular leakage by maintaining endothelial integrity.

PMID:34149436 | PMC:PMC8211987 | DOI:10.3389/fphar.2021.695009

Biomed Pharmacother. 2021 Jun 16;141:111835. doi: 10.1016/j.biopha.2021.111835. Online ahead of print.

ABSTRACT

Thymic stromal lymphopoietin (TSLP) produced by mast cells is involved in allergic inflammation pathogenesis. Chloroquine (CQ) is known to be an anti-malarial drug; however, additional protective functions of CQ have been discovered. This study aims to clarify an anti-inflammatory effect of CQ through modulating TSLP levels using an in vitro model of phorbol myristate acetate (PMA) + A23187-activated human mast cell line (HMC-1) and an in vivo model of PMA-irritated ear edema. CQ treatment reduced the production and mRNA expression levels of TSLP in activated HMC-1 cells. CQ down-regulated caspase-1 (CASP1), MAPKs, and NF-κB levels enhanced by stimulation with PMA + A23187. Moreover, ear thickness in ear edema was suppressed following CQ treatment. CQ decreased CASP1 and NF-κB levels in the ear tissue. TSLP levels in the ear tissue and serum were reduced following CQ treatment. Collectively, the above findings elucidate that CQ inhibits the pro-inflammatory mechanisms of TSLP via the down-regulation of distinct intracellular signaling cascade in mast cells. Therefore, CQ may have protective roles against TSLP-mediated inflammatory disorders.

PMID:34146852 | DOI:10.1016/j.biopha.2021.111835

Toxicol Sci. 2021 Jun 17:kfab079. doi: 10.1093/toxsci/kfab079. Online ahead of print.

ABSTRACT

Coronavirus disease 2019 (COVID-19) continues to spread across the globe, with numerous clinical trials underway seeking to develop and test effective COVID-19 therapies, including remdesivir. Several ongoing studies have reported hydroxychloroquine-induced cardiotoxicity, including development of torsade de pointes (TdP). Meanwhile, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are expected to serve as a tool for assessing drug-induced cardiotoxicity, such as TdP and contraction impairment. However, the cardiotoxicity of COVID-19 treatments has not been fully assessed using hiPSC-CMs. In the present study, we focused on drug repurposing with various modes of actions and examined the TdP risk associated with COVID-19 treatments using field potential using multi-electrode array (MEA) system and motion analysis with hiPSC-CMs. Hydroxychloroquine induced early after depolarization, while remdesivir, favipiravir, camostat and ivermectin had little effect on field potentials. We then analyzed electromechanical window (EMw), which is defined as the difference between field potential and contraction-relaxation durations. Hydroxychloroquine decreased EMw of hiPSC-CMs in a concentration-dependent manner. In contrast, other drugs have little effect. Our data suggest that hydroxychloroquine has proarrhythmic risk and other drugs have low proarrhythmic risk. Thus, hiPSC-CMs represent a useful tool for assessing the comprehensive cardiotoxicity caused by COVID-19 treatments in non-clinical settings.

PMID:34142159 | DOI:10.1093/toxsci/kfab079

Nat Biotechnol. 2021 Jun 17. doi: 10.1038/s41587-021-00946-z. Online ahead of print.

ABSTRACT

Drug discovery focused on target proteins has been a successful strategy, but many diseases and biological processes lack obvious targets to enable such approaches. Here, to overcome this challenge, we describe a deep learning-based efficacy prediction system (DLEPS) that identifies drug candidates using a change in the gene expression profile in the diseased state as input. DLEPS was trained using chemically induced changes in transcriptional profiles from the L1000 project. We found that the changes in transcriptional profiles for previously unexamined molecules were predicted with a Pearson correlation coefficient of 0.74. We examined three disorders and experimentally tested the top drug candidates in mouse disease models. Validation showed that perillen, chikusetsusaponin IV and trametinib confer disease-relevant impacts against obesity, hyperuricemia and nonalcoholic steatohepatitis, respectively. DLEPS can generate insights into pathogenic mechanisms, and we demonstrate that the MEK-ERK signaling pathway is a target for developing agents against nonalcoholic steatohepatitis. Our findings suggest that DLEPS is an effective tool for drug repurposing and discovery.

PMID:34140681 | DOI:10.1038/s41587-021-00946-z

Neuroscience. 2021 Jun 14:S0306-4522(21)00305-5. doi: 10.1016/j.neuroscience.2021.06.013. Online ahead of print.

ABSTRACT

Clinical trials of new drugs for Alzheimer's disease (AD) have ended with disappointing results with tremendous resources and time. Repositioning of existing anti-cancer EGFR inhibitors in various preclinical AD models has gained growing attention in recent years because hyperactivation of epidermal growth factor receptors (EGFR) has been implicated in many neurodegenerative disorders, including AD. Many recent studies have established that EGFR inhibition suppresses reactive astrocytes, enhances autophagy, ameliorates Aβ toxicity, neuroinflammation, and regenerates axonal degradation. However, there is no incontrovertible neuroprotective proof using EGFR inhibitors due to many under-explored signaling transductions, poor blood-brain barrier permeability of the most tested drugs, and disappointing outcomes of most clinical trials. This has caused debate about the possible involvement of EGFR inhibitors in future clinical trials. In this perspective article, we recap recent studies to merge data on the neuroprotective effects of EGFR inhibition. By consequent analysis of previous data, we notably find the under-investigated neuroprotective pathways that highlighting the importance of additional research of EGFR inhibitors in attempts to be repurposed as burgeoning therapeutic strategies AD. Finally, we will discuss future prospective challenges in the repositioning of EGFR inhibitors in AD.

PMID:34139302 | DOI:10.1016/j.neuroscience.2021.06.013

Adv Exp Med Biol. 2021 Jun 18. doi: 10.1007/5584_2021_652. Online ahead of print.

ABSTRACT

This article aims to present how the advanced solutions of artificial intelligence and precision medicine work together to refine medical management. Multi-omics seems the most suitable approach for biological analysis of data on precision medicine and artificial intelligence. We searched PubMed and Google Scholar databases to collect pertinent articles appearing up to 5 March 2021. Genetics, oncology, radiology, and the recent coronavirus disease (COVID-19) pandemic were chosen as representative fields addressing the cross-compliance of artificial intelligence (AI) and precision medicine based on the highest number of articles, topicality, and interconnectedness of the issue. Overall, we identified and perused 1572 articles. AI is a breakthrough that takes part in shaping the Fourth Industrial Revolution in medicine and health care, changing the long-time accepted diagnostic and treatment regimens and approaches. AI-based link prediction models may be outstandingly helpful in the literature search for drug repurposing or finding new therapeutical modalities in rapidly erupting wide-scale diseases such as the recent COVID-19.

PMID:34138457 | DOI:10.1007/5584_2021_652

Future Med Chem. 2021 Jun 17. doi: 10.4155/fmc-2021-0022. Online ahead of print.

ABSTRACT

Background: A comprehensive approach to drug repositioning will be required to overcome translational hurdles and identify more neuroprotective drugs. Results & methods: Gene Set Enrichment Analysis was applied to identify related pathways and enriched genes. Candidate genes were optimized using ToppGene, ToppGenet and pBRIT. From the perspective of the local structures, gene-domain-substructure-drug relationships were constructed. Using the MCODE algorithm and K-means clustering, 31 functional subnetworks were obtained, and 252 drugs with proposed neuroprotective function were identified. Using computational analysis, 72 substructures with different scores were found to correspond to neuroprotective functions. The protective effects of benidipine and barnidipine were confirmed in vitro. Conclusion: The authors' research has great potential to discover more neuroprotective drugs and obtain more information regarding mechanisms of action and functional substructures.

PMID:34137272 | DOI:10.4155/fmc-2021-0022

Porto Biomed J. 2021 Jun 14;6(3):e132. doi: 10.1097/j.pbj.0000000000000132. eCollection 2021 May-Jun.

ABSTRACT

As an innovative therapeutic strategy, drug repurposing affords old, approved, and already established drugs a chance at new indications. In the wake of the COVID-19 pandemic and the accompanied urgency for a lasting treatment, drug repurposing has come in handy to stem the debilitating effects of the disease. Among other therapeutic options currently in clinical trials, chloroquine (CQ) and the hydroxylated analogue, hydroxychloroquine (HCQ) have been frontline therapeutic options in most formal and informal clinical settings with varying degrees of efficacy against this life-threatening disease. Their status in randomized clinical trials is related to the biochemical and pharmacological profiles as validated by in vitro, in vivo and case studies. With the aim to bear a balance for their use in the long run, this review not only synopsizes findings from recent studies on the degrees of efficacy and roles of CQ/HCQ as potential anti-COVID-19 agents but also highlights our perspectives for their consideration in rational drug repositioning and use.

PMID:34136717 | PMC:PMC8202634 | DOI:10.1097/j.pbj.0000000000000132

Front Mol Biosci. 2021 May 31;8:670815. doi: 10.3389/fmolb.2021.670815. eCollection 2021.

ABSTRACT

The 2019-2020 winter was marked by the emergence of a new coronavirus (SARS-CoV-2) related disease (COVID-19), which started in Wuhan, China. Its high human-to-human transmission ability led to a worldwide spread within few weeks and has caused substantial human loss. Mechanical antiviral control approach, drug repositioning, and use of COVID-19 convalescent plasmas (CPs) were the first line strategies utilized to mitigate the viral spread, yet insufficient. The urgent need to contain this deadly pandemic has led searchers and pharmaceutical companies to develop vaccines. However, not all vaccines manufactured are safe. Besides, an alternative and effective treatment option for such an infectious disease would include pure anti-viral neutralizing monoclonal antibodies (NmAbs), which can block the virus at specific molecular targets from entering cells by inhibiting virus-cell structural complex formation, with more safety and efficiency than the CP. Indeed, there is a lot of molecular evidence about the protector effect and the use of molecular feature-based NmAbs as promising therapeutics to contain COVID-19. Thus, from the scientific publication database screening, we here retrieved antibody-related papers and summarized the repertory of characterized NmAbs against SARS-CoV-2, their molecular neutralization mechanisms, and their immunotherapeutic pros and cons. About 500 anti-SARS-CoV-2 NmAbs, characterized through competitive binding assays and neutralization efficacy, were reported at the writing time (January 2021). All NmAbs bind respectively to SARS-CoV-2 S and exhibit high molecular neutralizing effects against wild-type and/or pseudotyped virus. Overall, we defined six NmAb groups blocking SARS-CoV-2 through different molecular neutralization mechanisms, from which five potential neutralization sites on SARS-CoV-2 S protein are described. Therefore, more efforts are needed to develop NmAbs-based cocktails to mitigate COVID-19.

PMID:34136533 | PMC:PMC8201996 | DOI:10.3389/fmolb.2021.670815

Front Med (Lausanne). 2021 May 31;8:684020. doi: 10.3389/fmed.2021.684020. eCollection 2021.

ABSTRACT

The coronavirus disease (COVID-19), a worldwide pandemic, is caused by the severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). At this moment in time, there are no specific therapeutics available to combat COVID-19. Drug repurposing and identification of naturally available bioactive molecules to target SARS-CoV-2 are among the key strategies to tackle the notorious virus. The enzyme RNA-dependent RNA polymerase (RdRp) performs a pivotal role in replicating the virus. RdRp is a prime target for Remdesivir and other nucleotides analog-based antiviral drugs. In this study, we showed three bioactive molecules from tea (epicatechin-3,5-di-O-gallate, epigallocatechin-3,5-di-O-gallate, and epigallocatechin-3,4-di-O-gallate) that showed better interaction with critical residues present at the catalytic center and the NTP entry channel of RdRp than antiviral drugs Remdesivir and Favipiravir. Our computational approach to identify these molecules included molecular docking studies, followed by robust molecular dynamics simulations. All the three molecules are readily available in tea and could be made accessible along with other medications to treat COVID-19 patients. However, these results require validation by further in vitro and in vivo studies.

PMID:34136511 | PMC:PMC8200525 | DOI:10.3389/fmed.2021.684020

Saudi Pharm J. 2021 May;29(5):434-445. doi: 10.1016/j.jsps.2021.04.004. Epub 2021 Apr 16.

ABSTRACT

Drug repositioning is defined as a process to identify a new application for drugs. This approach is critical as it takes advantage of well-known pharmacokinetics, pharmacodynamics, and toxicity profiles of the drugs; thus, the chance of their future failure decreases, and the cost of their development and the required time for their approval are reduced. Anthelmintics, which are antiparasitic drugs, have recently demonstrated promising anticancer effects in vitro and in vivo. This literature review focuses on the potential of anthelmintics for repositioning in the treatment of cancers. It also discusses their pharmacokinetics and pharmacodynamics as antiparasitic drugs, proposed anticancer mechanisms, present development conditions, challenges in cancer therapy, and strategies to overcome these challenges.

PMID:34135669 | PMC:PMC8180459 | DOI:10.1016/j.jsps.2021.04.004

CPT Pharmacometrics Syst Pharmacol. 2021 Jun 16. doi: 10.1002/psp4.12670. Online ahead of print.

ABSTRACT

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by pulmonary vascular remodeling leading to increased pulmonary vascular resistance and pulmonary arterial pressure. PAH is a highly morbid cardiopulmonary disease adversely affecting lifespan and quality of life. Despite increased awareness and advances of medical therapies in recent decades, long-term prognosis and survival remain poor for patients with PAH. Novel therapies that can target the underlying pathobiology of PAH and reverse pulmonary vascular remodeling are clearly needed. In this study, we develop a network module-based framework to examine potential drug repositioning for PAH. The rationale for this approach is that in order to have therapeutic effects, the targets of potential drugs must be significantly proximate to the disease module of interest in the human protein-protein interactome. Based on 15 existing drugs for treating PAH, our framework integrates drug-drug interactions, drug-drug chemical similarity, drug targets, and PAH disease proteins into the human interactome, and prioritizes candidate drugs for PAH. We identified 53 drugs that could potentially be repurposed for PAH. Many of these candidates have strong literature support. Compared to black-box-like machine learning models, network module-based drug repositioning can provide mechanistic insights into how repositioned drugs can target the underlying pathobiological mechanisms of PAH.

PMID:34132494 | DOI:10.1002/psp4.12670

Phytother Res. 2021 Jun 16. doi: 10.1002/ptr.7157. Online ahead of print.

ABSTRACT

In the current study, the pivotal roles of serum and glucocorticoid-induced protein kinase (SGK1) and NF-kB related signalings known as prognostic biomarkers in cervical cancers were explored in the antitumor effect of a ginseng saponin metabolite compound K (CK) in HeLa and SiHa cervical cancer cells. CK exerted significant cytotoxicity, induced sub-G1 accumulation, and attenuated the expression of proPoly (ADP-ribose) polymerase (pro-PARP) and Pro-cysteine aspartyl-specific protease (pro-caspase3) in HeLa cells more than in SiHa cells. CK inhibited phosphorylation of SGK1 and its upstream genes, phosphoinositide 3-kinases (PI3K), and phosphoinositide-dependent kinase-1 (PDK1) in HeLa cells. In addition, CK suppressed the phosphorylation of SGK1, NF-κB, and inhibitor of kappa B (IκB) and also NF-κB target genes such as X-linked inhibitor of apoptosis protein and B-cell lymphoma 2 (Bcl-2) in HeLa cells. Notably, Immunoprecipitation revealed that SGK1 binds to PI3K or PDK1 and also CK disturbed the binding between SGK1 and PI3K or PDK1 in HeLa cells. Furthermore, PI3K inhibitor LY294002 decreased expression of PI3K, p-PDK1, p-SGK1, and pro-caspase3 and SGK1 inhibitor GSK650394 also reduced expression of NF-κB and pro-caspase3 just like CK in HeLa cells. Overall, these findings suggest that CK induces apoptosis via suppression of PI3K/PDK1/SGK1 and NF-κB signaling axis.

PMID:34132431 | DOI:10.1002/ptr.7157

Lab Chip. 2021 Jun 16. doi: 10.1039/d1lc00039j. Online ahead of print.

ABSTRACT

Metastasis is a frequent complication of cancer and accounts for more than 60% of patients' mortality. Despite technological advancements, treatment options are still limited. Ion channels participate in the regulation of cell adhesion, whilst the regulation of cell adhesion further controls metastasis formation. However, to develop a new ion channel inhibitor targeting metastasis takes tremendous effort and resources; therefore, drug repurposing is an emerging strategy in oncology. In previous studies, we have developed a metal-based nanoslit surface plasmon resonance (SPR) platform to examine the influence of drugs on the cell adhesion process. In this work, we developed a scanner-based cell adhesion kinetic examination (CAKE) system that is capable of monitoring the cell adhesion process by measuring color changes of SPR biosensors. The system's performance was demonstrated by screening the anti-metastasis ability of compounds from a commercial ion-channel inhibitor library. Out of the 274 compounds from the inhibitor library, zinc pyrithione (ZPT) and terfenadine were demonstrated to influence CL1-5 cell adhesion. The cell responses to the two compounds were then compared with those by traditional cell adhesion assays where similar behavior was observed. Further investigation of the two compounds using wound healing and transwell assays was performed and inhibitions of both cell migration and invasion by the two compounds were also observed. The results indicate that ZPT and terfenadine are potential candidates for anti-metastasis drugs. Our work has demonstrated the label-free drug screening ability of our CAKE system for finding potential drugs for cancer treatment.

PMID:34132296 | DOI:10.1039/d1lc00039j

Recent Pat Anticancer Drug Discov. 2021 Jun 15. doi: 10.2174/1574892816666210615163417. Online ahead of print.

ABSTRACT

BACKGROUND: Over recent years, there has been an increasing focus on the repurposing of existing, well-known medications for new, novel usage. One such drug is metformin, typically utilized in the management of diabetes, which demonstrates a positive relationship between its administration and lower cancer morbidity and mortality. Based on this finding, numerous studies and clinical trials have been conducted to examine the potential usage of metformin as an anticancer agent.

OBJECTIVE: This article aims to summarize metformin's anticancer effects through reviewing its literature and patents, with a focus on its potential to be repurposed for cancer therapy.

METHODS: Various databases were examined using keywords, 'Metformin' and 'Cancer'. Research articles were collected through the PubMed database, clinical trials were obtained from the Clinical Trials database, and patents were collected through the Google Patents database.

RESULTS: Metformin shows antineoplastic activity in various models. These anticancer properties appear to synergize with existing chemotherapeutics, which allows for a reduction in drug dosage without losing potency while minimizing adverse effects. Numerous patents on metformin have been filed which claim various combination therapies, delivery methods, and uses for cancer therapy, displaying an increasing interest in metformin's anticancer potential.

CONCLUSION: Preclinical studies, along with early phase clinical trials, have examined antitumor properties of metformin on a variety of cancers. Metformin's anticancer effects are well documented, demonstrating a great promise in improving current cancer therapies. However, there is a significant lack of late phase clinical trials, specifically those involving non-diabetic cancer patients, and therefore further research in this area is required.

PMID:34132186 | DOI:10.2174/1574892816666210615163417

New Gener Comput. 2021 Jun 10:1-25. doi: 10.1007/s00354-021-00128-0. Online ahead of print.

ABSTRACT

The Coronavirus disease (COVID-19) is an infectious disease caused by the newly discovered Severe Acute Respiratory Syndrome Coronavirus two (SARS-CoV-2). Most of the people do not have the acquired immunity to fight this virus. There is no specific treatment or medicine to cure the disease. The effects of this disease appear to vary from individual to individual, right from mild cough, fever to respiratory disease. It also leads to mortality in many people. As the virus has a very rapid transmission rate, the entire world is in distress. The control and prevention of this disease has evolved as an urgent and critical issue to be addressed through technological solutions. The Healthcare industry therefore needs support from the domain of artificial intelligence (AI). AI has the inherent capability of imitating the human brain and assisting in decision-making support by automatically learning from input data. It can process huge amounts of data quickly without getting tiresome and making errors. AI technologies and tools significantly relieve the burden of healthcare professionals. In this paper, we review the critical role of AI in responding to different research challenges around the COVID-19 crisis. A sample implementation of a powerful probabilistic machine learning (ML) algorithm for assessment of risk levels of individuals is incorporated in this paper. Other pertinent application areas such as surveillance of people and hotspots, mortality prediction, diagnosis, prognostic assistance, drug repurposing and discovery of protein structure, and vaccine are presented. The paper also describes various challenges that are associated with the implementation of AI-based tools and solutions for practical use.

PMID:34131359 | PMC:PMC8191724 | DOI:10.1007/s00354-021-00128-0

Sci Rep. 2021 Jun 15;11(1):12537. doi: 10.1038/s41598-021-91629-x.

ABSTRACT

Differentiation therapy is attracting increasing interest in cancer as it can be more specific than conventional chemotherapy approaches, and it has offered new treatment options for some cancer types, such as treating acute promyelocytic leukaemia (APL) by retinoic acid. However, there is a pressing need to identify additional molecules which act in this way, both in leukaemia and other cancer types. In this work, we hence developed a novel transcriptional drug repositioning approach, based on both bioinformatics and cheminformatics components, that enables selecting such compounds in a more informed manner. We have validated the approach for leukaemia cells, and retrospectively retinoic acid was successfully identified using our method. Prospectively, the anti-parasitic compound fenbendazole was tested in leukaemia cells, and we were able to show that it can induce the differentiation of leukaemia cells to granulocytes in low concentrations of 0.1 μM and within as short a time period as 3 days. This work hence provides a systematic and validated approach for identifying small molecules for differentiation therapy in cancer.

PMID:34131166 | DOI:10.1038/s41598-021-91629-x

NPJ Genom Med. 2021 Jun 15;6(1):50. doi: 10.1038/s41525-021-00216-6.

ABSTRACT

Many of genes mediating Known Drug-Disease Association (KDDA) are escaped from experimental detection. Identifying of these genes (hidden genes) is of great significance for understanding disease pathogenesis and guiding drug repurposing. Here, we presented a novel computational tool, called KDDANet, for systematic and accurate uncovering the hidden genes mediating KDDA from the perspective of genome-wide functional gene interaction network. KDDANet demonstrated the competitive performances in both sensitivity and specificity of identifying genes in mediating KDDA in comparison to the existing state-of-the-art methods. Case studies on Alzheimer's disease (AD) and obesity uncovered the mechanistic relevance of KDDANet predictions. Furthermore, when applied with multiple types of cancer-omics datasets, KDDANet not only recapitulated known genes mediating KDDAs related to cancer, but also revealed novel candidates that offer new biological insights. Importantly, KDDANet can be used to discover the shared genes mediating multiple KDDAs. KDDANet can be accessed at http://www.kddanet.cn and the code can be freely downloaded at https://github.com/huayu1111/KDDANet .

PMID:34131148 | DOI:10.1038/s41525-021-00216-6

ACS Infect Dis. 2021 Jun 15. doi: 10.1021/acsinfecdis.1c00017. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 168 million cases and 3.4 million deaths to date, while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here, we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent antiviral activity across multiple orthogonal assays. Hits include known antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as kinases and proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with remdesivir, the only antiviral approved by the FDA to treat COVID-19, highlighting the potential for combination therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective antiviral mono- or combination therapies to treat COVID-19.

PMID:34129317 | DOI:10.1021/acsinfecdis.1c00017