Front Oncol. 2021 May 10;11:653621. doi: 10.3389/fonc.2021.653621. eCollection 2021.

ABSTRACT

To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatment. These strategies, capable of either sensitizing or protecting tissues, target either tumor or normal tissue and are often focused on modulating of tissue oxygenation, hypoxia-inducible factor (HIF) stabilization, glucose metabolism, mitochondrial function and the redox balance. Several compounds or therapies are still in under (pre-)clinical development, while others are already used in clinical practice. Here, we describe different strategies from bench to bedside to optimize the therapeutic ratio through modulation of the cellular metabolism. This review gives an overview of the current state on development and the mechanism of action of modulators affecting cellular metabolism with the aim to improve the radiotherapy response on tumors or to protect the normal tissue and therefore contribute to an improved therapeutic ratio.

PMID:34041023 | PMC:PMC8143268 | DOI:10.3389/fonc.2021.653621

Front Pharmacol. 2021 May 10;12:624844. doi: 10.3389/fphar.2021.624844. eCollection 2021.

ABSTRACT

The increasing risks of radiological or nuclear attacks or associated accidents have served to renew interest in developing radiation medical countermeasures. The development of prospective countermeasures and the subsequent gain of Food and Drug Administration (FDA) approval are invariably time consuming and expensive processes, especially in terms of generating essential human data. Due to the limited resources for drug development and the need for expedited drug approval, drug developers have turned, in part, to the strategy of repurposing agents for which safety and clinical data are already available. Approval of drugs that are already in clinical use for one indication and are being repurposed for another indication is inherently faster and more cost effective than for new agents that lack regulatory approval of any sort. There are four known growth factors which have been repurposed in the recent past as radiomitigators following the FDA Animal Rule: Neupogen, Neulasta, Leukine, and Nplate. These four drugs were in clinic for several decades for other indications and were repurposed. A large number of additional agents approved by various regulatory authorities for given indications are currently under investigation for dual use for acute radiation syndrome or for delayed pathological effects of acute radiation exposure. The process of drug repurposing, however, is not without its own set of challenges and limitations.

PMID:34040517 | PMC:PMC8141805 | DOI:10.3389/fphar.2021.624844

Sci Rep. 2021 May 26;11(1):11049. doi: 10.1038/s41598-021-90296-2.

ABSTRACT

The SARS-CoV-2 pandemic has challenged researchers at a global scale. The scientific community's massive response has resulted in a flood of experiments, analyses, hypotheses, and publications, especially in the field of drug repurposing. However, many of the proposed therapeutic compounds obtained from SARS-CoV-2 specific assays are not in agreement and thus demonstrate the need for a singular source of COVID-19 related information from which a rational selection of drug repurposing candidates can be made. In this paper, we present the COVID-19 PHARMACOME, a comprehensive drug-target-mechanism graph generated from a compilation of 10 separate disease maps and sources of experimental data focused on SARS-CoV-2/COVID-19 pathophysiology. By applying our systematic approach, we were able to predict the synergistic effect of specific drug pairs, such as Remdesivir and Thioguanosine or Nelfinavir and Raloxifene, on SARS-CoV-2 infection. Experimental validation of our results demonstrate that our graph can be used to not only explore the involved mechanistic pathways, but also to identify novel combinations of drug repurposing candidates.

PMID:34040048 | DOI:10.1038/s41598-021-90296-2

J Hepatol. 2021 Jul;75 Suppl 1:S118-S134. doi: 10.1016/j.jhep.2021.01.024.

ABSTRACT

Patients with decompensated cirrhosis are currently managed through targeted strategies aimed at preventing or treating specific complications. In contrast, a disease-modifying agent should, by definition, be aimed at globally addressing 'decompensated cirrhosis'. To be defined as a disease-modifying agent in decompensated cirrhosis, interventions need to demonstrate an unequivocal benefit on the course of disease in well-designed and adequately powered randomised clinical trials with hard endpoints (i.e. patient survival). These trials also need to define the target population, dosage and timing of administration, factors guiding treatment, temporary or permanent stopping rules, transferability to daily clinical practice, cost-effectiveness, and global treatment access. By eliminating the underlying cause of cirrhosis, aetiologic treatments can still influence the course of decompensated disease by halting or slowing down disease progression or even inducing reversion to the compensated state. In contrast, there remains an unmet clinical need for disease-modifying agents which can antagonise key pathophysiological mechanisms of decompensated cirrhosis, such as portal hypertension, gut translocation, circulatory dysfunction, systemic inflammation, and immunological dysfunction. However, in the last few years, the repurposing of "old drugs" that have already been prescribed for more limited indications in hepatology or for other diseases has provided a few candidates, including human albumin, statins, and poorly absorbable oral antibiotics, which are under further evaluation in large-scale randomised clinical trials. New disease-modifying agents are also expected to be identified in the next decade through the systematic repurposing of existing drugs and the development of novel molecules which are currently undergoing pre-clinical or early clinical testing.

PMID:34039483 | DOI:10.1016/j.jhep.2021.01.024

Drug Dev Ind Pharm. 2021 May 26:1-27. doi: 10.1080/03639045.2021.1934863. Online ahead of print.

ABSTRACT

Indomethacin (IND) is one of the supporting drug candidates for colonic targeting but it belongs to BCS class II category presenting a challenge in optimal targeting at the colonic site. To overcome this challenge, we sought to prepare a pH-dependent soluble ternary solid dispersion (SD) of IND of improved solubility and dissolution rate at the colon without the need for a coating. The current study focuses on the preparation of binary SDs of API (IND) with shellac (SSB 55) and Eudragit FS 100 (EFS) and ternary mixtures of IND, SSB 55 together with a new grade of HPMC (A15). Respective SDs were prepared via HME to achieve gastric protection and improved dissolution performance including maintenance of supersaturation. The SDs were characterized and tested for in-vitro dissolution performance using a pH shift dissolution method from 1.1, 5.5, 6.8, and 7.4. A ternary extrudate of IND, SSB 55, and A15 showed improved protection below pH 5.5 with a complete release of 99.5% at pH 7.4 compared to IND neat and binary extrudates from IND-A15, IND-SSB 55, and IND-EFS. It was attributed to an increased level of intermolecular interaction confirmed by ATR-IR and was studied for stability. It was found that in a ternary mixture containing IND, A15 and SSB 55 an increased hydrogen bonding interaction is present, which resulted in improved dissolution performance compared to binary mixtures. Therefore, ternary SDs proved to be a promising concept for future development of colon targeting of poorly soluble drugs.

PMID:34038307 | DOI:10.1080/03639045.2021.1934863

Curr Med Chem. 2021 May 25. doi: 10.2174/0929867328666210525162730. Online ahead of print.

ABSTRACT

Prostate cancer (PCa) carries a growing burden on society. Lack of curative treatment and poor prognosis among patients with advanced PCa implies an urgent need for novel and improved drug identification. This is hampered by the disease's high molecular heterogeneity and complex molecular pathophysiology, resulting in drugs being efficient in few patients and cancer developing resistance to treatment. De novo drug discovery has proven to be complex and challenging. Along with technological advancements (mainly linked to -omics approaches) that allow for comprehensive characterization of the molecular changes underlying disease, and considering respective developments in bioinformatics, computational drug repurposing has emerged as a promising approach to shorten the way from discovery to clinical application and address the disease molecular complexity. With this article, we aimed at reviewing recent studies in which drugs/ compounds for PCa were defined through the investigation of molecular profiling (-omics) data and application of drug repurposing strategies. A brief overview of the technical requirements and associated challenges with the latter are also provided. For that purpose, a literature search was conducted using the PubMed database. Numerous drugs/ compounds have been proposed as potential PCa therapeutics, mostly based on the investigation of genomics and transcriptomics data. In most cases, further assessment in disease models is required. Since ultimately proteins are targeted by drugs, expanding on the use of proteomics profiling data (alone or in combination with other -omics) is expected to advance further defining new/repurposed drugs for PCa.

PMID:34036903 | DOI:10.2174/0929867328666210525162730

Evid Based Complement Alternat Med. 2021 May 4;2021:6694698. doi: 10.1155/2021/6694698. eCollection 2021.

ABSTRACT

BACKGROUND: Butylphthalide (NBP), approved by the China National Medical Products Administration (NMPA) for the treatment of ischemic stroke (IS), showed pleiotropic potentials against central nervous system (CNS) diseases, including neuroprotection and cognitive deficits improvement. However, the effects and corresponding modes of action were not fully explored. This study was designed to investigate the potential of NBP against IS-associated CNS diseases based on network pharmacology (NP) and molecular docking (MD).

METHODS: IS was inputted as the index disease to retrieve the "associated diseases" in DisGeNET. Three-database-based IS genes were obtained and integrated (DisGeNET, Malacards, and OMIM). Then, IS-associated genes were identified by combining these genes. Meanwhile, PubMed references and online databases were applied to identify NBP target genes. The IS-related disease-disease association (DDA) network and NBP-disease regulation network were constructed and analyzed in Cytoscape. In silico MD and references were used to validate the binding affinity of NBP with critical targets and the potential of NBP against certain IS-related CNS disease regulation.

RESULTS: 175 NBP target genes were obtained, while 312 IS-related disease genes were identified. 36 NBP target genes were predicted to be associated with IS-related CNS diseases, including Alzheimer's disease (AD), epilepsy, major depressive disorder (MDD), amyotrophic lateral sclerosis (ALS), and dementia. Six target genes (i.e., GRIN1, PTGIS, PTGES, ADRA1A, CDK5, and SULT1E1) indicating disease specificity index (DSI) >0.5 showed certain to good degree binding affinity with NBP, ranging from -9.2 to -6.7 kcal/mol. And the binding modes may be mainly related to hydrogen bonds and hydrophobic "bonds." Further literature validations inferred that these critical NBP targets had a tight association with AD, epilepsy, ALS, and depression.

CONCLUSIONS: Our study proposed a drug-target-disease integrated method to predict the drug repurposing potentials to associated diseases by application of NP and MD, which could be an attractive alternative to facilitate the development of CNS disease therapies. NBP may be promising and showed potentials to be repurposed for treatments for AD, epilepsy, ALS, and depression, and further investigations are warranted to be carefully designed and conducted.

PMID:34035826 | PMC:PMC8116153 | DOI:10.1155/2021/6694698

Neuropsychopharmacology. 2021 May 25. doi: 10.1038/s41386-021-01023-4. Online ahead of print.

ABSTRACT

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.

PMID:34035472 | DOI:10.1038/s41386-021-01023-4

Sci Rep. 2021 May 25;11(1):10887. doi: 10.1038/s41598-021-90456-4.

ABSTRACT

Osteosarcoma is one of the most aggressive bone tumors in children and adolescents. Development of effective therapeutic options is still lacking due to the complexity of the genomic background. In previous work, we applied a proteomics-guided drug repurposing to explore potential treatments for osteosarcoma. Our follow-up study revealed an FDA-approved immunosuppressant drug, mycophenolate mofetil (MMF) targeting inosine-5'-phosphate dehydrogenase (IMPDH) enzymes, has an anti-tumor effect that appeared promising for further investigation and clinical trials. Profiling of IMPDH2 and hypoxanthine-guanine phosphoribosyltransferase (HPRT), key purine-metabolizing enzymes, could deepen understanding of the importance of purine metabolism in osteosarcoma and provide evidence for expanded use of MMF in the clinic. In the present study, we investigated levels of IMPDH2, and HPRT in biopsy of 127 cases and post-chemotherapy tissues in 20 cases of high-grade osteosarcoma patients using immunohistochemical (IHC) analysis. Cox regression analyses were performed to determine prognostic significance of all enzymes. The results indicated that low levels of HPRT were significantly associated with a high Enneking stage (P = 0.023) and metastatic status (P = 0.024). Univariate and multivariate analyses revealed that patients with low HPRT expression have shorter overall survival times [HR 1.70 (1.01-2.84), P = 0.044]. Furthermore, high IMPDH2/HPRT ratios were similarly associated with shorter overall survival times [HR 1.67 (1.02-2.72), P = 0.039]. Levels of the enzymes were also examined in post-chemotherapy tissues. The results showed that high IMPDH2 expression was associated with shorter metastasis-free survival [HR 7.42 (1.22-45.06), P = 0.030]. These results suggest a prognostic value of expression patterns of purine-metabolizing enzymes for the pre- and post-chemotherapy period of osteosarcoma treatment.

PMID:34035425 | DOI:10.1038/s41598-021-90456-4

J Biomol Struct Dyn. 2021 May 25:1-13. doi: 10.1080/07391102.2021.1930160. Online ahead of print.

ABSTRACT

Chlamydia felis is the primary cause of chronic conjunctivitis without respiratory infections in cats, making conjunctiva as its primary target. It is a Gram-negative obligate intracellular bacterium that cannot survive outside the host cell. C. felis can be found worldwide and its zoonotic potential is a known phenomenon. The scope of zoonoses, its scale, and their impact experiencing today has no historical precedence. Among the identified 1415 human pathogens 868 have a zoonotic origin making it to 61%. Although with appropriate drug administration there are instances of re-occurrence of chlamydial infections, the emergence of heterotypic antimicrobial resistance to antibiotics targeting rRNA due to mutations has further complicated the diagnosis and treatment of chlamydial infections. Ribonucleotide-diphosphate reductase subunit beta (RNR) is one of the crucial target proteins of the bacterial pathogens essential in the synthesis of deoxyribonucleotides. Our current study primarily focuses on modeling the target structure through homology modeling. Further, the validated model is complexed with the specific inhibitor Cladribine through sequence-based ligand search. Docking of the identified ligand was performed to identify the different modes of interactions with amino acids present in the prioritized binding pockets. Validation of the binding modes is carried out through molecular dynamics (MD) simulations for the best binding pose with a high binding score. MD simulation study demonstrated the stability of the docked complex considered in this study. The findings from this study may be helpful in drug repurposing and novel drug research in the scenario of resistance to currently practiced antibiotics.Communicated by Ramaswamy H. Sarma.

PMID:34032189 | DOI:10.1080/07391102.2021.1930160

Comput Biol Chem. 2021 May 7;92:107505. doi: 10.1016/j.compbiolchem.2021.107505. Online ahead of print.

ABSTRACT

Hyperlipidemia causes diseases like cardiovascular disease, cancer, Type II Diabetes and Alzheimer's disease. Drugs that specifically target HL associated diseases are required for treatment. 34 KEGG pathways targeted by lipid lowering drugs were used to construct a directed protein-protein interaction network and driver nodes were determined using CytoCtrlAnalyser plugin of Cytoscape 3.6. The involvement of driver nodes of HL in other diseases was verified using GWAS. The central nodes of the network and 34 overrepresented pathways had a critical role in Hyperlipidemia. The PI3K-AKT signalling pathway, non-essentiality, non-centrality and approved drug target status were the predominant features of the driver nodes. Next, a Random Forest classifier was trained on 1445 molecular descriptors calculated using PaDEL for 50 approved lipid lowering and 84 lipid raising drugs as the positive and negative training set respectively. The classifier showed average accuracy of 76.8 % during 5-fold cross validation with AUC of 0.79 ± 0.06 for the ROC curve. The classifier was applied to select molecules with favourable properties for lipid lowering from the 130 approved drugs interacting with the identified driver nodes. We have integrated diverse network data and machine learning to predict repurposing of nine drugs for treatment of HL associated diseases.

PMID:34030115 | DOI:10.1016/j.compbiolchem.2021.107505

Inform Med Unlocked. 2021;24:100604. doi: 10.1016/j.imu.2021.100604. Epub 2021 May 19.

ABSTRACT

The recent outbreak of coronavirus pandemic (COVID-19) introduced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has greatly affected the global public health. This pandemic disease became particularly threatening after the start of a new wave. Vaccines of tested efficacy to stop COVID-19 infection are being investigated vigorously worldwide. Currently, some specific drugs have been authorized for COVID-19, but the improvement of antivirals requires time. Hence, a faster way of treatment is done by drug repurposing. Repurposing of drugs is promising for treating and reducing the symptoms of the disease, and it a fast, easy, and safe method to address the crisis, because of their previously known applications. Some antimalarial drugs, especially chloroquine and hydroxychloroquine, have been repurposed, as they exhibited promising results in vitro and in vivo. This article investigates repurposed antimalarial drugs, focusing on their antiviral mechanisms of action, effects in combinations, trial results, and their side effects.

PMID:34028468 | PMC:PMC8132553 | DOI:10.1016/j.imu.2021.100604

Curr Med Chem. 2021;28(12):2303-2304. doi: 10.2174/092986732812210419080559.

NO ABSTRACT

PMID:34028345 | DOI:10.2174/092986732812210419080559

Front Cardiovasc Med. 2021 May 5;8:650278. doi: 10.3389/fcvm.2021.650278. eCollection 2021.

ABSTRACT

Heart failure (HF) patients often suffer from multiple comorbidities, such as diabetes, atrial fibrillation, depression, chronic obstructive pulmonary disease, and chronic kidney disease. The coexistance of comorbidities usually leads to multi morbidity and poor prognosis. Treatments for HF patients with multi morbidity are still an unmet clinical need, and finding an effective therapy strategy is of great value. HF can lead to comorbidity, and in return, comorbidity may promote the progression of HF, creating a vicious cycle. This reciprocal correlation indicates there may be some common causes and biological mechanisms. Metabolism remodeling and chronic inflammation play a vital role in the pathophysiological processes of HF and comorbidities, indicating metabolism and inflammation may be the links between HF and comorbidities. In this review, we comprehensively discuss the major underlying mechanisms and therapeutic implications for comorbidities of HF. We first summarize the potential role of metabolism and inflammation in HF. Then, we give an overview of the linkage between common comorbidities and HF, from the perspective of epidemiological evidence to the underlying metabolism and inflammation mechanisms. Moreover, with the help of bioinformatics, we summarize the shared risk factors, signal pathways, and therapeutic targets between HF and comorbidities. Metabolic syndrome, aging, deleterious lifestyles (sedentary behavior, poor dietary patterns, smoking, etc.), and other risk factors common to HF and comorbidities are all associated with common mechanisms. Impaired mitochondrial biogenesis, autophagy, insulin resistance, and oxidative stress, are among the major mechanisms of both HF and comorbidities. Gene enrichment analysis showed the PI3K/AKT pathway may probably play a central role in multi morbidity. Additionally, drug targets common to HF and several common comorbidities were found by network analysis. Such analysis has already been instrumental in drug repurposing to treat HF and comorbidity. And the result suggests sodium-glucose transporter-2 (SGLT-2) inhibitors, IL-1β inhibitors, and metformin may be promising drugs for repurposing to treat multi morbidity. We propose that targeting the metabolic and inflammatory pathways that are common to HF and comorbidities may provide a promising therapeutic strategy.

PMID:34026868 | PMC:PMC8131678 | DOI:10.3389/fcvm.2021.650278

Front Mol Biosci. 2021 May 7;8:673053. doi: 10.3389/fmolb.2021.673053. eCollection 2021.

ABSTRACT

G protein-coupled receptors (GPCRs) are the largest human membrane receptor family regulating a wide range of cell signaling. For this reason, GPCRs are highly desirable drug targets, with approximately 40% of prescribed medicines targeting a member of this receptor family. The structural homology of GPCRs and the broad spectrum of applications of GPCR-acting drugs suggest an investigation of the cross-activity of a drug toward different GPCR receptors with the aim of rationalizing drug side effects, designing more selective and less toxic compounds, and possibly proposing off-label therapeutic applications. Herein, we present an original in silico approach named "Computational Profiling for GPCRs" (CPG), which is able to represent, in a one-dimensional (1D) string, the physico-chemical properties of a ligand-GPCR binding interaction and, through a tailored alignment algorithm, repurpose the ligand for a different GPCR. We show three case studies where docking calculations and pharmacological data confirm the drug repurposing findings obtained through CPG on 5-hydroxytryptamine receptor 2B, beta-2 adrenergic receptor, and M2 muscarinic acetylcholine receptor. The CPG code is released as a user-friendly graphical user interface with numerous options that make CPG a powerful tool to assist the drug design of GPCR ligands.

PMID:34026848 | PMC:PMC8138314 | DOI:10.3389/fmolb.2021.673053

Front Microbiol. 2021 May 6;12:579806. doi: 10.3389/fmicb.2021.579806. eCollection 2021.

ABSTRACT

Widespread antibiotic resistance has been reported in enterococcal pathogens that cause life-threatening infections. Enterococci species rapidly acquire resistance and the pace of new antibiotic development is slow. Drug repurposing is a promising approach in solving this problem. Bithionol (BT) is a clinically approved anthelminthic drug. In this study, we found that BT showed significant antimicrobial and antibiofilm effects against Enterococcus faecalis and vancomycin-resistant Entercococcus faecium in vitro, in a dose-dependent manner, by disrupting the integrity of the bacterial cell membranes. Moreover, BT effectively reduced the bacterial load in mouse organs when combined with conventional antibiotics in a peritonitis infection model. Thus, BT has shown potential as a therapeutic agent against E. faecalis- and vancomycin-resistant E. faecium-related infections.

PMID:34025592 | PMC:PMC8138570 | DOI:10.3389/fmicb.2021.579806

Front Pharmacol. 2021 May 7;12:675287. doi: 10.3389/fphar.2021.675287. eCollection 2021.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is an infectious disease that rapidly spread throughout the world leading to high mortality rates. Despite the knowledge of previous diseases caused by viruses of the same family, such as MERS and SARS-CoV, management and treatment of patients with COVID-19 is a challenge. One of the best strategies around the world to help combat the COVID-19 has been directed to drug repositioning; however, these drugs are not specific to this new virus. Additionally, the pathophysiology of COVID-19 is highly heterogeneous, and the way of SARS-CoV-2 modulates the different systems in the host remains unidentified, despite recent discoveries. This complex and multifactorial response requires a comprehensive therapeutic approach, enabling the integration and refinement of therapeutic responses of a given single compound that has several action potentials. In this context, natural compounds, such as Curcumin, have shown beneficial effects on the progression of inflammatory diseases due to its numerous action mechanisms: antiviral, anti-inflammatory, anticoagulant, antiplatelet, and cytoprotective. These and many other effects of curcumin make it a promising target in the adjuvant treatment of COVID-19. Hence, the purpose of this review is to specifically point out how curcumin could interfere at different times/points during the infection caused by SARS-CoV-2, providing a substantial contribution of curcumin as a new adjuvant therapy for the treatment of COVID-19.

PMID:34025433 | PMC:PMC8138567 | DOI:10.3389/fphar.2021.675287

Infect Dis (Lond). 2021 May 22:1-18. doi: 10.1080/23744235.2021.1924397. Online ahead of print.

ABSTRACT

Long COVID or post-COVID-19 syndrome first gained widespread recognition among social support groups and later in scientific and medical communities. This illness is poorly understood as it affects COVID-19 survivors at all levels of disease severity, even younger adults, children, and those not hospitalized. While the precise definition of long COVID may be lacking, the most common symptoms reported in many studies are fatigue and dyspnoea that last for months after acute COVID-19. Other persistent symptoms may include cognitive and mental impairments, chest and joint pains, palpitations, myalgia, smell and taste dysfunctions, cough, headache, and gastrointestinal and cardiac issues. Presently, there is limited literature discussing the possible pathophysiology, risk factors, and treatments in long COVID, which the current review aims to address. In brief, long COVID may be driven by long-term tissue damage (e.g. lung, brain, and heart) and pathological inflammation (e.g. from viral persistence, immune dysregulation, and autoimmunity). The associated risk factors may include female sex, more than five early symptoms, early dyspnoea, prior psychiatric disorders, and specific biomarkers (e.g. D-dimer, CRP, and lymphocyte count), although more research is required to substantiate such risk factors. While preliminary evidence suggests that personalized rehabilitation training may help certain long COVID cases, therapeutic drugs repurposed from other similar conditions, such as myalgic encephalomyelitis or chronic fatigue syndrome, postural orthostatic tachycardia syndrome, and mast cell activation syndrome, also hold potential. In sum, this review hopes to provide the current understanding of what is known about long COVID.

PMID:34024217 | DOI:10.1080/23744235.2021.1924397

Nucleic Acids Res. 2021 May 22:gkab385. doi: 10.1093/nar/gkab385. Online ahead of print.

ABSTRACT

Although several tools facilitating in silico drug design are available, their results are usually difficult to integrate with publicly available information or require further processing to be fully exploited. The rational design of multi-target ligands (polypharmacology) and the repositioning of known drugs towards unmet therapeutic needs (drug repurposing) have raised increasing attention in drug discovery, although they usually require careful planning of tailored drug design strategies. Computational tools and data-driven approaches can help to reveal novel valuable opportunities in these contexts, as they enable to efficiently mine publicly available chemical, biological, clinical, and disease-related data. Based on these premises, we developed LigAdvisor, a data-driven webserver which integrates information reported in DrugBank, Protein Data Bank, UniProt, Clinical Trials and Therapeutic Target Database into an intuitive platform, to facilitate drug discovery tasks as drug repurposing, polypharmacology, target fishing and profiling. As designed, LigAdvisor enables easy integration of similarity estimation results with clinical data, thereby allowing a more efficient exploitation of information in different drug discovery contexts. Users can also develop customizable drug design tasks on their own molecules, by means of ligand- and target-based search modes, and download their results. LigAdvisor is publicly available at https://ligadvisor.unimore.it/.

PMID:34023895 | DOI:10.1093/nar/gkab385

Drug Discov Today. 2021 May 20:S1359-6446(21)00240-3. doi: 10.1016/j.drudis.2021.05.008. Online ahead of print.

ABSTRACT

Effective therapeutics to combat emerging viral infections are an unmet need. Historically, treatments for chronic viral infections with single drugs have not been successful, as exemplified by HIV and hepatitis C virus (HCV) infections. Combination therapy for these diseases has led to improved clinical outcomes with dramatic reductions in viral load, morbidity, and mortality. Drug combinations can enhance therapeutic efficacy through additive, and ideally synergistic, effects for emerging and re-emerging viruses, such as influenza, severe acute respiratory syndrome-coronavirus (SARS-CoV), Middle East respiratory syndrome (MERS)-CoV, Ebola, Zika, and SARS-coronavirus 2 (CoV-2). Although novel drug development through traditional pipelines remains a priority, in the interim, effective synergistic drug candidates could be rapidly identified by drug-repurposing screens, facilitating accelerated paths to clinical testing and potential emergency use authorizations.

PMID:34023496 | DOI:10.1016/j.drudis.2021.05.008