Oncogene. 2021 May 10. doi: 10.1038/s41388-021-01822-5. Online ahead of print.

ABSTRACT

Tyrosine kinase inhibitors (TKIs) are used as targeted drugs for advanced renal cell carcinoma (RCC), although most cases eventually progress by acquiring resistance. Cancer stemness plays critical roles in tumor aggressiveness and therapeutic resistance, and dipeptidyl peptidase IV (DPP4) has been recently identified as a cancer stemness-related protein. A question arises whether DPP4 contributes to TKI efficacy in RCC. We established patient-derived RCC spheroids and showed that DPP4 expression is associated with stemness-related gene expression. TKI sunitinib resistance was rescued by DPP4 inhibition using sitagliptin or specific siRNAs in RCC cells and tumors. DPP4 expression can be inducible by retinoic acid and repressed by ALDH1A inhibition. Among type 2 diabetes patients with clinical RCC tumors, higher TKI efficacy is observed in those bearing DPP4high tumors treated with DPP4 inhibitors. This study provides new insights into TKI resistance and drug repositioning of DPP4 inhibitor as a promising strategy for advanced RCC.

PMID:33972682 | DOI:10.1038/s41388-021-01822-5

Pharmacol Rep. 2021 May 10. doi: 10.1007/s43440-021-00228-0. Online ahead of print.

ABSTRACT

INTRODUCTION: Drug repurposing is the need of the hour considering the medical emergency caused by the COVID-19 pandemic. Recently, cytokine storm by the host immune system has been linked with high viral load, loss of lung function, acute respiratory distress syndrome (ARDS), multiple organ failure, and subsequent fatal outcome.

OBJECTIVE: This study aimed to identify potential FDA approved drugs that can be repurposed for COVID-19 treatment using an in-silico analysis.

METHODS: In this study, virtual screening of selected FDA approved drugs was performed by targeting the main protease (Mpro) of SARS-CoV-2 and the key molecules involved in the 'Cytokine storm' in COVID-19 patients. Based on our preliminary screening supported by extensive literature search, we selected FDA approved drugs to target the SARS-CoV-2 main protease (Mpro) and the key players of cytokine storm, TNF-α, IL-6, and IL-1β. These compounds were examined based on systematic docking studies and further validated using a combination of molecular dynamics simulations and molecular mechanic/generalized/Born/Poisson-Boltzmann surface area (MM/G/P/BSA) free energy calculations.

RESULTS: Based on the findings, Rifampicin and Letermovir appeared as the most promising drug showing a very good binding affinity with the main protease of SARS-CoV-2 and TNF-α, IL-6, and IL-1β. However, it is pertinent to mention here that our findings need further validation by in vitro analysis and clinical trials.

CONCLUSION: This study provides an insight into the drug repurposing approach in which several FDA approved drugs were examined to inhibit COVID-19 infection by targeting the main protease of SARS-COV-2 and the cytokine storm.

PMID:33970450 | DOI:10.1007/s43440-021-00228-0

Front Pharmacol. 2021 Apr 22;12:631584. doi: 10.3389/fphar.2021.631584. eCollection 2021.

ABSTRACT

Real-world healthcare data hold the potential to identify therapeutic solutions for progressive diseases by efficiently pinpointing safe and efficacious repurposing drug candidates. This approach circumvents key early clinical development challenges, particularly relevant for neurological diseases, concordant with the vision of the 21st Century Cures Act. However, to-date, these data have been utilized mainly for confirmatory purposes rather than as drug discovery engines. Here, we demonstrate the usefulness of real-world data in identifying drug repurposing candidates for disease-modifying effects, specifically candidate marketed drugs that exhibit beneficial effects on Parkinson's disease (PD) progression. We performed an observational study in cohorts of ascertained PD patients extracted from two large medical databases, Explorys SuperMart (N = 88,867) and IBM MarketScan Research Databases (N = 106,395); and applied two conceptually different, well-established causal inference methods to estimate the effect of hundreds of drugs on delaying dementia onset as a proxy for slowing PD progression. Using this approach, we identified two drugs that manifested significant beneficial effects on PD progression in both datasets: rasagiline, narrowly indicated for PD motor symptoms; and zolpidem, a psycholeptic. Each confers its effects through distinct mechanisms, which we explored via a comparison of estimated effects within the drug classification ontology. We conclude that analysis of observational healthcare data, emulating otherwise costly, large, and lengthy clinical trials, can highlight promising repurposing candidates, to be validated in prospective registration trials, beneficial against common, late-onset progressive diseases for which disease-modifying therapeutic solutions are scarce.

PMID:33967767 | PMC:PMC8100658 | DOI:10.3389/fphar.2021.631584

Front Pharmacol. 2021 Apr 22;12:621676. doi: 10.3389/fphar.2021.621676. eCollection 2021.

ABSTRACT

Objectives: No specific treatment has been approved for COVID-19. Lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ) have been used with poor results, and a trial showed advantages of combined antiviral therapy vs. single antivirals. The aim of the study was to assess the effectiveness of the combination of antivirals (LPV/r and HCQ) or their single use in COVID-19 hospitalized patients vs. standard of care (SoC). Methods: Patients ≥18 years with SARS-CoV-2 infection, defined as positive RT-PCR from nasal/oropharyngeal (NP/OP) swab or positive serology, admitted at L. Spallanzani Institute (Italy) were included. Primary endpoint: time to invasive ventilation/death. Secondary endpoint: time to two consecutive negative SARS-CoV-2 PCRs in NP/OP swabs. In order to control for measured confounders, a marginal Cox regression model with inverse probability weights was used. Results: A total of 590 patients were included in the analysis: 36.3% female, 64 years (IQR 51-76), and 91% with pneumonia. Cumulative probability of invasive ventilation/death at 14 days was 21.2% (95% CI 17.6, 24.7), without difference between SOC, LPV/r, hydroxychloroquine, HCQ + LPV/r, and SoC. The risk of invasive ventilation/death in the groups appeared to vary by baseline ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2). Overall cumulative probability of confirmed negative nasopharyngeal swabs at 14 days was 44.4% (95% CI 38.9, 49.9), without difference between groups. Conclusion: In this retrospective analysis, we found no difference in the rate of invasive ventilation/death or viral shedding by different strategies, as in randomized trials performed to date. Moreover, even the combination HCQ + LPV/r did not show advantages vs. SoC.

PMID:33967755 | PMC:PMC8100580 | DOI:10.3389/fphar.2021.621676

Front Pharmacol. 2021 Apr 23;12:608778. doi: 10.3389/fphar.2021.608778. eCollection 2021.

ABSTRACT

High-risk neuroblastoma (NB) remains a significant therapeutic challenge facing current pediatric oncology patients. Structural variants such as gene fusions have shown an initial promise in enhancing mechanistic understanding of NB and improving survival rates. In this study, we performed a comprehensive in silico investigation on the translational ability of gene fusions for patient stratification and treatment development for high-risk NB patients. Specifically, three state-of-the-art gene fusion detection algorithms, including ChimeraScan, SOAPfuse, and TopHat-Fusion, were employed to identify the fusion transcripts in a RNA-seq data set of 498 neuroblastoma patients. Then, the 176 high-risk patients were further stratified into four different subgroups based on gene fusion profiles. Furthermore, Kaplan-Meier survival analysis was performed, and differentially expressed genes (DEGs) for the redefined high-risk group were extracted and functionally analyzed. Finally, repositioning candidates were enriched in each patient subgroup with drug transcriptomic profiles from the LINCS L1000 Connectivity Map. We found the number of identified gene fusions was increased from clinical the low-risk stage to the high-risk stage. Although the technical concordance of fusion detection algorithms was suboptimal, they have a similar biological relevance concerning perturbed pathways and regulated DEGs. The gene fusion profiles could be utilized to redefine high-risk patient subgroups with significant onset age of NB, which yielded the improved survival curves (Log-rank p value ≤ 0.05). Out of 48 enriched repositioning candidates, 45 (93.8%) have antitumor potency, and 24 (50%) were confirmed with either on-going clinical trials or literature reports. The gene fusion profiles have a discrimination power for redefining patient subgroups in high-risk NB and facilitate precision medicine-based drug repositioning implementation.

PMID:33967751 | PMC:PMC8105087 | DOI:10.3389/fphar.2021.608778

Virus Res. 2021 May 5:198372. doi: 10.1016/j.virusres.2021.198372. Online ahead of print.

NO ABSTRACT

PMID:33965275 | DOI:10.1016/j.virusres.2021.198372

BMC Pharmacol Toxicol. 2021 May 7;22(1):27. doi: 10.1186/s40360-021-00495-w.

ABSTRACT

BACKGROUND: Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice.

METHODS: First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.).

RESULTS: In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice.

CONCLUSIONS: Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive.

PMID:33962676 | DOI:10.1186/s40360-021-00495-w

Virus Res. 2021 May 4:198444. doi: 10.1016/j.virusres.2021.198444. Online ahead of print.

ABSTRACT

Drug repurposing is an important source of new antivirals because many compounds used to treat a variety of pathologies also hamper viral infections. Habitually, silver nanoparticles (AgNPs) have been used to treat bacterial and fungal infections and their antiviral properties have been also reported. In this work, we have studied the antiviral capacity of AgNPs in cells infected with Bunyamwera virus (BUNV), the prototype of the Bunyavirales order. This group of viruses contains important pathogens for humans, animals and plants. Incubation of BUNV-infected Vero cells with non-toxic concentrations of AgNPs, reduced the production of extracellular infectious viruses in up to three orders of magnitude. With a combination of imaging techniques, we have visualized the intracellular distribution of AgNPs in mock- and BUNV-infected cells and studied their effects on intracellular organelles. In mock-infected cells and at short times post-incubation, AgNPs were detected inside nuclei and mitochondria by transmission electron microscopy (TEM). At long times post-treatment, they accumulated inside lysosome-like organelles. Cell compartments did not exhibit any appreciable ultrastructural alterations after incubation with AgNPs. In BUNV-infected cells, AgNPs attached to extracellular virions, that showed a disrupted morphology. Inside cells, they were detected inside the nucleus, in mitochondria and around characteristic Golgi-associated, single-membrane spherules. These membranous structures are the replication organelles (ROs) of bunyaviruses and contain active viral replication complexes (VRCs). Compared to normal spherules that are round, compact and have an electron-dense core, spherules in AgNPs-treated cells were deformed and their core was electron-lucent. Interestingly, in BUNV-infected cells treated with the typical antiviral ribavirin (RBV), spherules with VRCs exhibit also an anomalous morphology and an electron-lucent core. Both AgNPs and RBV might interfere with BUNV-induced dismantling of cell nucleoli and with the intercellular propagation of large groups of virions, a mechanism of BUNV transmission observed for the first time in cultured cells. Our results point to silver nanoparticles as good candidates for antiviral therapy, either alone or in combination with other antiviral drugs, such as RBV-related compounds.

PMID:33961898 | DOI:10.1016/j.virusres.2021.198444

Curr Cardiol Rep. 2021 May 7;23(6):62. doi: 10.1007/s11886-021-01484-5.

ABSTRACT

PURPOSE OF REVIEW: Drug development has evolved over the years from being one-at-a-time to be massive screens in an industrial manner. Bringing a new therapeutic agent from concept to bedside can take a decade and cost billions of dollars-with most concepts failing along the way. Of the few compounds that make it to clinical testing, less than one out of eight make it to approval. This traditional drug development pipeline is challenging for prevalent diseases and makes the development of new therapeutics for rare diseases financially intractable.

RECENT FINDINGS: Repurposing of drugs is an alternative to identify new applications for the thousands of compounds that have already been approved for clinical use. There is now a range of strategies for such efforts that leverage clinical data, pharmacologic data, and/or genomic or transcriptomic data. These strategies, together with examples, are detailed in this review. Drug repurposing bypasses the pre-clinical work and thereby opens up the opportunity to provide targeted treatment at a fraction of the cost that is accompanied with the development from ideation to full approval. Such an approach makes drug discovery for any disease process more efficient but holds particular promise for rare diseases for which there is little to no other viable drug development channel.

PMID:33961142 | DOI:10.1007/s11886-021-01484-5

Br J Pharmacol. 2021 May 7. doi: 10.1111/bph.15452. Online ahead of print.

ABSTRACT

COVID-19 is a complex disease, and many difficulties are faced today especially in the proper choice of pharmacological treatments. The role of antiviral agents for COVID-19 is still being investigated and evidence for immunomodulatory and anti-inflammatory drugs is quite conflicting, whereas the use of corticosteroids is supported by robust evidence. The use of heparins in hospitalized critically ill patients is preferred over other anticoagulants. There are conflicting data on the use of convalescent plasma and vitamin D. According to the World Health Organization (WHO), many vaccines are in Phase III clinical trials, and some of them have already received marketing approval in European countries and in the United States. In conclusion, drug repurposing has represented the main approach recently used in the treatment of patients with COVID-19. At this moment, analysis of efficacy and safety data of drugs and vaccines used in real-life context is strongly needed.

PMID:33960398 | DOI:10.1111/bph.15452

In Silico Pharmacol. 2021 May 4;9(1):35. doi: 10.1007/s40203-021-00093-y. eCollection 2021.

ABSTRACT

ABSTRACT: Hepatitis E virus (HEV) infection is emerging in Cameroon and represents one of the most common causes of acute hepatitis and jaundice. Moreover, earlier reports showed evidence of falciparum malaria/HEVcoexistence. Although the Sofosbuvir/Ribavirin combination was recently proposed in the treatment of HEV-infected patients, no specific antiviral drug has been approved so far, thereby urging the search for new therapies. Fortunately, drug repurposing offers a good alternative to this end. In this study, we report the in silico and in vitro activities of 8 licensed antimalarial drugs and two anti-hepatitis C virus agents used as references (Sofosbuvir, and Ribavirin), for repurposing as antiviral inhibitors against HEV. Compounds were docked against five HEV-specific targets including the Zinc-binding non-structural protein (6NU9), RNA-dependent RNA polymerase (RdRp), cryoEM structure of HEV VLP, genotype 1 (6LAT), capsid protein ORF-2, genotype 3 (2ZTN), and the E2s domain of genotype 1 (3GGQ) using the iGEMDOCK software and their pharmacokinetic profiles and toxicities were predicted using ADMETlab2.0. Their in vitro effects were also assessed on a gt 3 p6Gluc replicon system using the luciferase reporter assay. The docking results showed that Sofosbuvir had the best binding affinities with 6NU9 (- 98.22 kcal/mol), RdRp (- 113.86 kcal/mol), 2ZTN (- 106.96 kcal/mol), while Ribavirin better collided with 6LAT (- 99.33 kcal/mol). Interestingly, Lumefantrine showed the best affinity with 3GGQ (-106.05 kcal/mol). N-desethylamodiaquine and Amodiaquine presented higher binding scores with 6NU9 (- 93.5 and - 89.9 kcal/mol respectively vs - 80.83 kcal/mol), while Lumefantrine had the greatest energies with RdRp (- 102 vs - 84.58), and Pyrimethamine and N-desethylamodiaquine had stronger affinities with 2ZTN compared to Ribavirin (- 105.17 and - 102.65 kcal/mol vs - 96.04 kcal/mol). The biological screening demonstrated a significant (P < 0.001) antiviral effect on replication with 1 µM N-desethylamodiaquine, the major metabolite of Amodiaquine. However, Lumefantrine showed no effect at the tested concentrations (1, 5, and 10 µM). The biocomputational analysis of the pharmacokinetic profile of both drugs revealed a low permeability of Lumefantrine and a specific inactivation by CYP3A2 which might partly contribute to the short half-time of this drug. In conclusion, Amodiaquine and Lumefantrine may be good antimalarial drug candidates for repurposing against HEV. Further in vitro and in vivo experiments are necessary to validate these predictions.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00093-y.

PMID:33959472 | PMC:PMC8093904 | DOI:10.1007/s40203-021-00093-y

Expert Opin Drug Discov. 2021 May 7:1-15. doi: 10.1080/17460441.2021.1918098. Online ahead of print.

ABSTRACT

Introduction: Drug design and discovery of new antivirals will always be extremely important in medicinal chemistry, taking into account known and new viral diseases that are yet to come. Although machine learning (ML) have shown to improve predictions on the biological potential of chemicals and accelerate the discovery of drugs over the past decade, new methods and their combinations have improved their performance and established promising perspectives regarding ML in the search for new antivirals.Areas covered: The authors consider some interesting areas that deal with different ML techniques applied to antivirals. Recent innovative studies on ML and antivirals were selected and analyzed in detail. Also, the authors provide a brief look at the past to the present to detect advances and bottlenecks in the area.Expert opinion: From classical ML techniques, it was possible to boost the searches for antivirals. However, from the emergence of new algorithms and the improvement in old approaches, promising results will be achieved every day, as we have observed in the case of SARS-CoV-2. Recent experience has shown that it is possible to use ML to discover new antiviral candidates from virtual screening and drug repurposing.

PMID:33957833 | DOI:10.1080/17460441.2021.1918098

Eur J Pharmacol. 2021 May 3:174144. doi: 10.1016/j.ejphar.2021.174144. Online ahead of print.

ABSTRACT

Zika virus (ZIKV) is a mosquito-borne flavivirus, that could cause congenital Zika syndrome (CZS), characterized by microcephaly, neurological complications and fetal deaths. No specific treatments for ZIKV are currently available, highlighting the urgent global need to identify and develop therapeutic agents. Drug repositioning of approved natural compounds can provide effective alternative solutions for novel antiviral development. The current study focused on curcumin, a component of turmeric known to exert diverse antiviral effects. We integrated in silico information from publicly available databases to predict interactions between curcumin and potential targets of ZIKV. In our network analysis, we identified four targets, TP53, AKT1, PTEN, and TNF, which were identified as potential targets associated with ZIKV. Based on retrieved targets, we performed molecular docking study and identified curcumin-TNF showed the strongest binding among four targets. The anti-Zika effects of curcumin were validated in vitro with the aid of antiviral and plaque reduction assay. Curcumin at concentrations ranging from 12.5-50 μM displayed significant antiviral activity in a dose-dependent manner (p < 0.05). In view of its natural abundance and prevalence in the human diet, curcumin holds significant promise for treatment of ZIKV infections.

PMID:33957087 | DOI:10.1016/j.ejphar.2021.174144

Brief Bioinform. 2021 May 6:bbab169. doi: 10.1093/bib/bbab169. Online ahead of print.

ABSTRACT

Two thousand nineteen novel coronavirus SARS-CoV-2, the pathogen of COVID-19, has caused a catastrophic pandemic, which has a profound and widespread impact on human lives and social economy globally. However, the molecular perturbations induced by the SARS-CoV-2 infection remain unknown. In this paper, from the perspective of omnigenic, we analyze the properties of the neighborhood perturbed by SARS-CoV-2 in the human interactome and disclose the peripheral and core regions of virus-host network (VHN). We find that the virus-host proteins (VHPs) form a significantly connected VHN, among which highly perturbed proteins aggregate into an observable core region. The non-core region of VHN forms a large scale but relatively low perturbed periphery. We further validate that the periphery is non-negligible and conducive to identifying comorbidities and detecting drug repurposing candidates for COVID-19. We particularly put forward a flower model for COVID-19, SARS and H1N1 based on their peripheral regions, and the flower model shows more correlations between COVID-19 and other two similar diseases in common functional pathways and candidate drugs. Overall, our periphery-core pattern can not only offer insights into interconnectivity of SARS-CoV-2 VHPs but also facilitate the research on therapeutic drugs.

PMID:33956950 | DOI:10.1093/bib/bbab169

IEEE/ACM Trans Comput Biol Bioinform. 2021 May 6;PP. doi: 10.1109/TCBB.2021.3077905. Online ahead of print.

ABSTRACT

Identifying drug-target interactions (DTIs) is an important step in the process of new drug discovery and drug repositioning. Accurate predictions for DTIs can improve efficiency in drug discovery and development. Although rapid advances in deep learning technologies have generated various computational methods, it is still appealing to further investigate how to design efficient networks for predicting DTIs. In this study, we propose an end-to-end deep learning method (called MHSADTI) to predict DTIs based on the graph attention network and multi-head self-attention mechanism models. First, the characteristics of drugs and proteins are extracted by the graph attention network model and multi-head self-attention mechanism, respectively. Then, the attention scores are used to consider which amino acid subsequence in a protein is more important for the drug to predict its interactions. Finally, we predict DTIs by a fully connected layer network after obtaining the feature vectors of drugs and proteins. The experiments in four datasets, human, C.elegans, DUD-E and DrugBank show our method outperforms the state-of-the-art method in terms of AUC, Precision, Recall, Recall, AUPR and F1-score. In addition, the case studies further demonstrate that our method can provide effective visualization to interpret the prediction results from biological insights.

PMID:33956632 | DOI:10.1109/TCBB.2021.3077905

J Healthc Eng. 2021 Apr 14;2021:6674744. doi: 10.1155/2021/6674744. eCollection 2021.

ABSTRACT

BACKGROUND: Osteoarthritis (OA) is a chronic and degenerative joint disease, which causes stiffness, pain, and decreased function. At the early stage of OA, nonsteroidal anti-inflammatory drugs (NSAIDs) are considered the first-line treatment. However, the efficacy and utility of available drug therapies are limited. We aim to use bioinformatics to identify potential genes and drugs associated with OA.

METHODS: The genes related to OA and NSAIDs therapy were determined by text mining. Then, the common genes were performed for GO, KEGG pathway analysis, and protein-protein interaction (PPI) network analysis. Using the MCODE plugin-obtained hub genes, the expression levels of hub genes were verified using quantitative real-time polymerase chain reaction (qRT-PCR). The confirmed genes were queried in the Drug Gene Interaction Database to determine potential genes and drugs.

RESULTS: The qRT-PCR result showed that the expression level of 15 genes was significantly increased in OA samples. Finally, eight potential genes were targetable to a total of 53 drugs, twenty-one of which have been employed to treat OA and 32 drugs have not yet been used in OA.

CONCLUSIONS: The 15 genes (including PTGS2, NLRP3, MMP9, IL1RN, CCL2, TNF, IL10, CD40, IL6, NGF, TP53, RELA, BCL2L1, VEGFA, and NOTCH1) and 32 drugs, which have not been used in OA but approved by the FDA for other diseases, could be potential genes and drugs, respectively, to improve OA treatment. Additionally, those methods provided tremendous opportunities to facilitate drug repositioning efforts and study novel target pharmacology in the pharmaceutical industry.

PMID:33953899 | PMC:PMC8060081 | DOI:10.1155/2021/6674744

J Environ Public Health. 2021 Apr 22;2021:6631721. doi: 10.1155/2021/6631721. eCollection 2021.

ABSTRACT

Novel coronavirus first appeared in Wuhan, China, in December 2019, and it speedily expanded globally. Some medications which are used to treat other diseases seem to be effective in treating COVID-19 even without explicit support. The existing drugs that are summarized in this review primarily focused on therapeutic agents that possessed activity against other RNA viruses such as MERS-CoV and SARS-CoV. Drug repurposing or repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs such as corticosteroids, RNA-dependent RNA polymerase inhibitors, interferons, protease inhibitors, ivermectin, melatonin, teicoplanin, and some others. A search for new drug/drug targets is underway. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The possible impact of biologics for the management of COVID19 is promising and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and various types of vaccines. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. This article aims to review the roles of existing drugs and drug targets for COVID-19 treatment.

PMID:33953756 | PMC:PMC8063850 | DOI:10.1155/2021/6631721

Sci Rep. 2021 May 5;11(1):9541. doi: 10.1038/s41598-021-89035-4.

ABSTRACT

Research on direct targets of traditional Chinese medicine (TCM) is the key to study the mechanism and material basis of it, but there is still no effective methods at present. We took Compound Danshen dropping pills (CDDP) as a study case to establish a strategy to identify significant direct targets of TCM. As a result, thirty potential active kinase targets of CDDP were identified. Nine of them had potential dose-dependent effects. In addition, the direct inhibitory effect of CDDP on three kinases, AURKB, MET and PIM1 were observed both on biochemical level and cellular level, which could not only shed light on the mechanisms of action involved in CDDP, but also suggesting the potency of drug repositioning of CDDP. Our results indicated that the research strategy including both in silico models and experimental validation that we built, were relatively efficient and reliable for direct targets identification for TCM prescription, which will help elucidating the mechanisms of TCM and promoting the modernization of TCM.

PMID:33953309 | DOI:10.1038/s41598-021-89035-4

Alzheimers Res Ther. 2021 May 5;13(1):96. doi: 10.1186/s13195-021-00831-6.

ABSTRACT

BACKGROUND: The relationship between cancer and dementia is triggering growing research interest. Several preclinical studies have provided the biological rationale for the repurposing of specific anticancer agents in Alzheimer's disease (AD), and a growing number of research protocols are testing their efficacy and safety/tolerability in patients with AD.

METHODS: The aim of the present systematic review was to provide an overview on the repurposing of approved anticancer drugs in clinical trials for AD by considering both ongoing and completed research protocols in all phases. In parallel, a systematic literature review was conducted on PubMed, ISI Web, and the Cochrane Library to identify published clinical studies on repurposed anticancer agents in AD.

RESULTS: Based on a structured search on the ClinicalTrials.gov and the EudraCT databases, we identified 13 clinical trials testing 11 different approved anticancer agents (five tyrosine kinase inhibitors, two retinoid X receptor agonists, two immunomodulatory agents, one histone deacetylase inhibitor, and one monoclonal antibody) in the AD continuum. The systematic literature search led to the identification of five published studies (one phase I, three phase II, and one phase IIb/III) reporting the effects of antitumoral treatments in patients with mild cognitive impairment or AD dementia. The clinical findings and the methodological characteristics of these studies are described and discussed.

CONCLUSION: Anticancer agents are triggering growing interest in the context of repurposed therapies in AD. Several clinical trials are underway, and data are expected to be available in the near future. To date, data emerging from published clinical studies are controversial. The promising results emerging from preclinical studies and identified research protocols should be confirmed and extended by larger, adequately designed, and high-quality clinical trials.

PMID:33952306 | DOI:10.1186/s13195-021-00831-6

Curr Med Chem. 2021 May 3. doi: 10.2174/0929867328666210504111442. Online ahead of print.

ABSTRACT

Human African and American trypanosomiasis are the vector-borne parasitic diseases that have killed millions of people early, and many people are still suffering from these neglected diseases. The causative agents of these infections are parasitic protozoans of the genus Trypanosoma. Current treatment regimens against these endemic diseases have several limitations in terms of safety, efficacy, route of administration, and some of them have lost efficacy due to the emergence of resistance in their respective parasites. In this review, the most promising compounds identified by different strategies of drug development against these neglected diseases, including target-based approach, the phenotypic high-throughput screening, the drug repurposing approach, and combination therapy, are emphasized. The potent heterocyclic compounds currently undergoing pre-clinical or clinical studies have also been assessed to ascertain an effective class of organic compounds having significant therapeutic potential against these tropical diseases. The molecular hybridization of outlined motifs may result in more active compounds and circumvent the development of resistance by specific targets in the future.

PMID:33949927 | DOI:10.2174/0929867328666210504111442