Genomics Proteomics Bioinformatics. 2021 Mar 17:S1672-0229(21)00074-7. doi: 10.1016/j.gpb.2020.06.023. Online ahead of print.

ABSTRACT

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes on the interactome network, which provides a new way for predicting drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

PMID:33744433 | DOI:10.1016/j.gpb.2020.06.023

J Infect Public Health. 2020 Oct 27;14(4):495-503. doi: 10.1016/j.jiph.2020.10.012. Online ahead of print.

ABSTRACT

BACKGROUND: A novel corona virus-2 disease has spread to 213 countries and territories across the globe. The corona pandemic has claimed more than 548,934 deaths worldwide till the evening of 8th of July 2020 and the number of confirmed cases is increasing at an alarming rate. Therefore, there is an urgent need to find a treatment or a vaccine for COVID-19 at the earliest. The aim of this mini-review is to give an overview of identified repurposed anti-COVID-19 drugs which are currently under clinical trials.

METHODS: A thorough literature survey was done to retrieve relevant information using various web based search engines such as Google, Google scholar, and various other electronic research databases such as PubMed, Medline, MeSh etc. The findings of the recently published articles, clinical trials, COVID-19 update by World Health Organization etc., and the opinion of the authors is summarized in this brief review. The antiviral medicinal plants were identified based on their use in Chinese/Indian indigenous systems of medicine, traditional use, published scientific phytochemical studies and/or their effectiveness against upper respiratory infections, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS).

RESULTS: The disease is just over six months old and effective prophylactic or therapeutic agents are yet to be developed for COVID-19. Thus, in the absence of an effective therapy, scientific community has rationally considered the drug repurposing approach for the development of anti COVID-19 drugs. Various studies and clinical trials involving antimalarial drugs, anti-HIV drugs, anti-hepatitis drugs, anti-parasitic drug, anti-inflammatory drugs, the combination of antimalarial and macrolide antibiotic and few other molecules identified through drug repurposing are currently underway to combat COVID-19. Due emphasis is also given to develop novel corona vaccines for the prophylaxis and to identify drugs for adjunct/supportive therapy. Several medicinal plants along with their major phytochemicals exhibiting antiviral activity are identified for further exploration. It is anticipated that these natural products might also play an important role in combating COVID-19.

CONCLUSIONS: Use of drug repurposing strategy to develop anti COVID-19 drugs and exploring antiviral medicinal plants as adjunct or supportive therapy appears to be a viable option. Therefore, it is the need of the hour to work in parallel on different strategies such as genetic engineering, in silico approach, herbal remedies and drug repositioning to achieve the common goal of finding a safe and effective treatment for COVID-19 at the earliest.

PMID:33743371 | DOI:10.1016/j.jiph.2020.10.012

Bioorg Chem. 2021 Mar 2;110:104786. doi: 10.1016/j.bioorg.2021.104786. Online ahead of print.

ABSTRACT

Studies displaying the combination of mefloquine (MFL) with anti-tuberculosis (TB) substances are limited in the literature. In this work, the effect of MFL-association with two first-line anti-TB drugs and six fluoroquinolones was evaluated against Mycobacterium tuberculosis drug resistant strains. MFL showed synergistic interaction with isoniazid, pyrazinamide, and several fluoroquinolones, reaching fractional inhibitory concentration indexes (FICIs) ranging from 0.03 to 0.5. In order to better understand the observed results, two approaches have been explored: (i) spectroscopic responses attributed to the effect of MFL on physicochemical properties related to a liposomal membrane model composed by soybean asolectin; (ii) molecular dynamics (MD) simulation data regarding MFL interaction with a membrane model based on PIM2, a lipid constituent of the mycobacterial cell wall. FTIR and NMR data showed that MFL affects expressively the region between the phosphate and the first methylene groups of soybean asolectin membranes, disordering these regions. MD simulations results detected high MFL density in the glycolipid interface and showed that the drug increases the membrane lateral diffusion, enhancing its permeability. The obtained results suggest that synergistic activities related to MFL are attributed to its effect of lipid disorder and membrane permeability enhancement.

PMID:33740676 | DOI:10.1016/j.bioorg.2021.104786

Bioinformatics. 2021 Mar 19:btab191. doi: 10.1093/bioinformatics/btab191. Online ahead of print.

ABSTRACT

MOTIVATION: Breast cancer is one of the leading causes of cancer deaths among women worldwide. It is necessary to develop new breast cancer drugs because of the shortcomings of existing therapies. The traditional discovery process is time-consuming and expensive. Repositioning of clinically approved drugs has emerged as a novel approach for breast cancer therapy. However, serendipitous or experiential repurposing cannot be used as a routine method.

RESULTS: In this study, we proposed a graph neural network model GraphRepur based on GraphSAGE for drug repurposing against breast cancer. GraphRepur integrated two major classes of computational methods, drug network-based and drug signature-based. The differentially expressed genes of disease, drug-exposure gene expression data, and the drug-drug links information were collected. By extracting the drug signatures and topological structure information contained in the drug relationships, GraphRepur can predict new drugs for breast cancer, outperforming previous state-of-the-art approaches and some classic machine learning methods. The high-ranked drugs have indeed been reported as new uses for breast cancer treatment recently.

AVAILABILITY: The source code of our model and datasets are available at: https://github.com/cckamy/GraphRepur and https://figshare.com/articles/software/GraphRepur_Breast_Cancer_Drug_Repurposing/14220050.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:33739367 | DOI:10.1093/bioinformatics/btab191

Front Genet. 2021 Feb 19;11:607824. doi: 10.3389/fgene.2020.607824. eCollection 2020.

ABSTRACT

Deep learning methods, which can predict the binding affinity of a drug-target protein interaction, reduce the time and cost of drug discovery. In this study, we propose a novel deep convolutional neural network called SE-OnionNet, with two squeeze-and-excitation (SE) modules, to computationally predict the binding affinity of a protein-ligand complex. The OnionNet is used to extract a feature map from the three-dimensional structure of a protein-drug molecular complex. The SE module is added to the second and third convolutional layers to improve the non-linear expression of the network to improve model performance. Three different optimizers, stochastic gradient descent (SGD), Adam, and Adagrad, were also used to improve the performance of the model. A majority of protein-molecule complexes were used for training, and the comparative assessment of scoring functions (CASF-2016) was used as the benchmark. Experimental results show that our model performs better than OnionNet, Pafnucy, and AutoDock Vina. Finally, we chose the macrophage migration inhibitor factor (PDB ID: 6cbg) to test the stability and robustness of the model. We found that the prediction results were not affected by the docking position, and thus, our model is of acceptable robustness.

PMID:33737946 | PMC:PMC7962986 | DOI:10.3389/fgene.2020.607824

Front Immunol. 2021 Mar 2;12:622001. doi: 10.3389/fimmu.2021.622001. eCollection 2021.

ABSTRACT

A relevant fraction of castration-resistant prostate cancers (CRPC) evolve into fatal neuroendocrine (NEPC) tumors in resistance to androgen deprivation and/or inhibitors of androgen receptor pathway. Therefore, effective drugs against both CRPC and NEPC are needed. We have previously described a dual role of mast cells (MCs) in prostate cancer, being capable to promote adenocarcinoma but also to restrain NEPC. This finding suggests that a molecule targeting both MCs and NEPC cells could be effective against prostate cancer. Using an in silico drug repurposing approach, here we identify the antiepileptic drug levetiracetam as a potential candidate for this purpose. We found that the protein target of levetiracetam, SV2A, is highly expressed by both NEPC cells and MCs infiltrating prostate adenocarcinoma, while it is low or negligible in adenocarcinoma cells. In vitro, levetiracetam inhibited the proliferation of NEPC cells and the degranulation of MCs. In mice bearing subcutaneous tumors levetiracetam was partially active on both NEPC and adenocarcinoma, the latter effect due to the inhibition of MMP9 release by MCs. Notably, in TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice subjected to surgical castration to mimic androgen deprivation therapy, levetiracetam reduced onset and frequency of both high grade prostatic intraepithelial neoplasia, adenocarcinoma and NEPC, thus increasing the number of cured mice showing only signs of tumor regression. Our results demonstrate that levetiracetam can directly restrain NEPC development after androgen deprivation, and that it can also block adenocarcinoma progression through the inhibition of some MCs functions. These findings open the possibility of further testing levetiracetam for the therapy of prostate cancer or of MC-mediated diseases.

PMID:33737929 | PMC:PMC7960782 | DOI:10.3389/fimmu.2021.622001

PLoS One. 2021 Mar 18;16(3):e0248553. doi: 10.1371/journal.pone.0248553. eCollection 2021.

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which is a novel human coronavirus strain (HCoV) was initially reported in December 2019 in Wuhan City, China. This acute infection caused pneumonia-like symptoms and other respiratory tract illness. Its higher transmission and infection rate has successfully enabled it to have a global spread over a matter of small time. One of the major concerns involving the SARS-COV-2 is the mutation rate, which enhances the virus evolution and genome variability, thereby making the design of therapeutics difficult. In this study, we identified the most common haplotypes from the haplotype network. The conserved genes and population level variants were analysed. Non-Structural Protein 10 (NSP10), Nucleoprotein, Papain-like protease (Plpro or NSP3) and 3-Chymotrypsin like protease (3CLpro or NSP5), which were conserved at the highest threshold, were used as drug targets for molecular dynamics simulations. Darifenacin, Nebivolol, Bictegravir, Alvimopan and Irbesartan are among the potential drugs, which are suggested for further pre-clinical and clinical trials. This particular study provides a comprehensive targeting of the conserved genes. We also identified the mutation frequencies across the viral genome.

PMID:33735271 | DOI:10.1371/journal.pone.0248553

Biomol Ther (Seoul). 2021 Mar 17. doi: 10.4062/biomolther.2021.032. Online ahead of print.

ABSTRACT

Novel coronavirus (SARS-CoV-2) has caused more than 100 million confirmed cases of human infectious disease (COVID-19) since December 2019 to paralyze our global community. However, only limited access has been allowed to COVID-19 vaccines and antiviral treatment options. Here, we report the efficacy of the anticancer drug pralatrexate against SARS-CoV-2. In Vero and human lung epithelial Calu-3 cells, pralatrexate reduced viral RNA copies of SARS-CoV-2 without detectable cytotoxicity, and viral replication was successfully inhibited in a dose-dependent manner. In a time-to-addition assay, pralatrexate treatment at almost half a day after infection also exhibited inhibitory effects on the replication of SARS-CoV-2 in Calu-3 cells. Taken together, these results suggest the potential of pralatrexate as a drug repurposing COVID-19 remedy.

PMID:33731494 | DOI:10.4062/biomolther.2021.032

PLoS One. 2021 Mar 17;16(3):e0247018. doi: 10.1371/journal.pone.0247018. eCollection 2021.

ABSTRACT

In this work, we performed an analysis of the networks of interactions between drugs and their targets to assess how connected the compounds are. For our purpose, the interactions were downloaded from the DrugBank database, and we considered all drugs approved by the FDA. Based on topological analysis of this interaction network, we obtained information on degree, clustering coefficient, connected components, and centrality of these interactions. We identified that this drug-target interaction network cannot be divided into two disjoint and independent sets, i.e., it is not bipartite. In addition, the connectivity or associations between every pair of nodes identified that the drug-target network is constituted of 165 connected components, where one giant component contains 4376 interactions that represent 89.99% of all the elements. In this regard, the histamine H1 receptor, which belongs to the family of rhodopsin-like G-protein-coupled receptors and is activated by the biogenic amine histamine, was found to be the most important node in the centrality of input-degrees. In the case of centrality of output-degrees, fostamatinib was found to be the most important node, as this drug interacts with 300 different targets, including arachidonate 5-lipoxygenase or ALOX5, expressed on cells primarily involved in regulation of immune responses. The top 10 hubs interacted with 33% of the target genes. Fostamatinib stands out because it is used for the treatment of chronic immune thrombocytopenia in adults. Finally, 187 highly connected sets of nodes, structured in communities, were also identified. Indeed, the largest communities have more than 400 elements and are related to metabolic diseases, psychiatric disorders and cancer. Our results demonstrate the possibilities to explore these compounds and their targets to improve drug repositioning and contend against emergent diseases.

PMID:33730052 | DOI:10.1371/journal.pone.0247018

Immune Netw. 2021 Feb 15;21(1):e7. doi: 10.4110/in.2021.21.e7. eCollection 2021 Feb.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 has severely impacted global health and economy. There is currently no effective approved treatment for COVID-19; although vaccines have been granted emergency use authorization in several countries, they are currently only administered to high-risk individuals, thereby leaving a gap in virus control measures. The scientific and clinical communities and drug manufacturers have collaborated to speed up the discovery of potential therapies for COVID-19 by taking advantage of currently approved drugs as well as investigatory agents in clinical trials. In this review, we stratified some of these candidates based on their potential targets in the progression of COVID-19 and discuss some of the results of ongoing clinical evaluations.

PMID:33728100 | PMC:PMC7937511 | DOI:10.4110/in.2021.21.e7

Exp Neurol. 2021 Mar 13:113697. doi: 10.1016/j.expneurol.2021.113697. Online ahead of print.

ABSTRACT

Epidermal growth factor receptor (EGFR) signaling plays a substantial role in learning and memory. The upregulation of EGFR has been embroiled in the pathophysiology of Alzheimer's disease (AD). Nevertheless, most of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have been extensively studied for non-CNS diseases such as cancer and rheumatoid arthritis. TKIs targeting-based research in neurodegenerative disorders sounds to be lagging behind those of other diseases. Hence, this study aims to explore the molecular signaling pathways and the efficacy of treatment with lapatinib ditosylate (LAP), as one of EGFR-TKIs that has not yet been investigated in AD, on cognitive decline induced by ovariectomy (OVX) with chronic administration of D-galactose (D-gal) in female Wistar albino rats. OVX rats were injected with 150 mg/kg/day D-gal ip for 8 weeks to induce AD. Administration of 100 mg/kg/day LAP p.o. for 3 weeks starting after the 8th week of D-gal administration improved memory and debilitated histopathological alterations. LAP decreased the expression of GFAP, p-tau, and Aβ 1-42. Besides, it reduced EGFR, HER-2, TNF-α, NOX-1, GluRII, p38 MAPK, and p-mTOR. LAP increased nitrite, and neuronal pro-survival transduction proteins; p-PI3K, p-AKT, and p-GSK-3β levels. Taken together, these findings suggest the role of LAP in ameliorating D-gal-induced AD in OVX rats via activating the pro-survival pathway; PI3K-Akt-GSK-3β, while inhibiting p-mTOR, NOX-1, and p38 MAPK pathways. Moreover, this research offered a significant opportunity to advance awareness of the repositioning of TKI anti-cancer drugs for the treatment of AD.

PMID:33727095 | DOI:10.1016/j.expneurol.2021.113697

Curr Drug Discov Technol. 2021 Mar 16. doi: 10.2174/1570163818666210316114331. Online ahead of print.

ABSTRACT

Since a decade, it has been observed that there is remarkable decrease in the quantum of novel clinically approved drugsin spite of modernization in research and development process. We have highlighted repositioning of drugs as a methodology that has found new therapeutic implications for clinically approved drugs but with different indications. This can be considered as an upbringing strategy to deliver timely and cost-effective solutions which still needexplorationtoget over the shortage of number of novel drugs reaching market. This review focuses on activity-based drug repositioning approach, which is used to explore new uses of known drugs that are already approved for specific indications and are now being used for other indications on the basis ofthe fact that single drug interacts with multiple targets. It also includes current research trends related to drug repositioning which depends on strong knowledge of medicinal chemistry and involves elucidation of mechanisms of action and validation of novel targets. The review highlights theimportance totheusage of computational tools and databases of various forms for drug repositioning purposes which have enhanced the ability to pose reasonable and testable hypotheses. The critical nature of this aspect is obvious in cases where data gathered from in vitro or animal models do not confirm in subsequent clinical trials. Hence, considering positive outcomes of drug repositioning, it can be surmised that this approach can serve as promising one that can develop into a robust drug discovery strategy.

PMID:33726652 | DOI:10.2174/1570163818666210316114331

JMIRx Med. 2020 Sep 30;1(1):e19583. doi: 10.2196/19583. eCollection 2020 Jan-Dec.

ABSTRACT

Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is an indispensable strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication) is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate (cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.

PMID:33724265 | PMC:PMC7954442 | DOI:10.2196/19583

Anal Bioanal Chem. 2021 Mar 15. doi: 10.1007/s00216-021-03230-w. Online ahead of print.

ABSTRACT

Schistosoma mansoni is a parasitic flatworm causing schistosomiasis, an infectious disease affecting several hundred million people worldwide. Schistosomes live dioeciously, and upon pairing with the male, the female starts massive egg production, which causes pathology. Praziquantel (PZQ) is the only drug used, but it has an inherent risk of resistance development. Therefore, alternatives are needed. In the context of drug repurposing, the cancer drug imatinib was tested, showing high efficacy against S. mansoni in vitro. Besides the gonads, imatinib mainly affected the integrity of the intestine in males and females. In this study, we investigated the potential uptake and distribution of imatinib in adult schistosomes including its distribution kinetics. To this end, we applied for the first time atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) for drug imaging in paired S. mansoni. Our results indicate that imatinib was present in the esophagus and intestine of the male as early as 20 min after in vitro exposure, suggesting an oral uptake route. After one hour, the drug was also found inside the paired female. The detection of the main metabolite, N-desmethyl imatinib, indicated metabolization of the drug. Additionally, a marker signal for the female ovary was successfully applied to facilitate further conclusions regarding organ tropism of imatinib. Our results demonstrate that AP-SMALDI MSI is a useful method to study the uptake, tissue distribution, and metabolization of imatinib in S. mansoni. The results suggest using AP-SMALDI MSI also for investigating other antiparasitic compounds and their metabolites in schistosomes and other parasites.

PMID:33723627 | DOI:10.1007/s00216-021-03230-w

Cell Discov. 2020 Mar 16;6(1):14. doi: 10.1038/s41421-020-0153-3.

ABSTRACT

Human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV) and 2019 novel coronavirus (2019-nCoV, also known as SARS-CoV-2), lead global epidemics with high morbidity and mortality. However, there are currently no effective drugs targeting 2019-nCoV/SARS-CoV-2. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we present an integrative, antiviral drug repurposing methodology implementing a systems pharmacology-based network medicine platform, quantifying the interplay between the HCoV-host interactome and drug targets in the human protein-protein interaction network. Phylogenetic analyses of 15 HCoV whole genomes reveal that 2019-nCoV/SARS-CoV-2 shares the highest nucleotide sequence identity with SARS-CoV (79.7%). Specifically, the envelope and nucleocapsid proteins of 2019-nCoV/SARS-CoV-2 are two evolutionarily conserved regions, having the sequence identities of 96% and 89.6%, respectively, compared to SARS-CoV. Using network proximity analyses of drug targets and HCoV-host interactions in the human interactome, we prioritize 16 potential anti-HCoV repurposable drugs (e.g., melatonin, mercaptopurine, and sirolimus) that are further validated by enrichment analyses of drug-gene signatures and HCoV-induced transcriptomics data in human cell lines. We further identify three potential drug combinations (e.g., sirolimus plus dactinomycin, mercaptopurine plus melatonin, and toremifene plus emodin) captured by the "Complementary Exposure" pattern: the targets of the drugs both hit the HCoV-host subnetwork, but target separate neighborhoods in the human interactome network. In summary, this study offers powerful network-based methodologies for rapid identification of candidate repurposable drugs and potential drug combinations targeting 2019-nCoV/SARS-CoV-2.

PMID:33723226 | DOI:10.1038/s41421-020-0153-3

Mol Cell Neurosci. 2021 Mar 12:103612. doi: 10.1016/j.mcn.2021.103612. Online ahead of print.

ABSTRACT

The multifactorial neurological condition called Alzheimer's disease (AD) primarily affects elderly individuals. Despite the calamitous consequences of AD, curative strategies for a regimen to apply remain inadequate as several factors contribute to AD etiology. Drug repurposing is an advance strategy prior to drug discovery as various effective drugs perform through alteration of multiple targets, and the present "poly-pharmacology" can be a curative approach to complex disorders. AD's multifactorial behavior actively encourages the hypothesis for a drug design approach focused on drug repurposing. In this study, we discovered that an antifungal drug, Caspofungin (CAS) is a potent Aβ aggregation inhibitor that displays significantly reduced toxicity associated with AD. Drug reprofiling and REMD simulations demonstrated that CAS interacts with the β-sheet section, known as Aβ amyloid fibrils hotspot. CAS leads to destabilization of β-sheet and, conclusively, in its devaluation. Later, in vitro experiments were acquired in which the fibrillar volume was reduced for CAS-treated Aβ peptide. For the first time ever, this study has determined an antifungal agent as the Aβ amyloid aggregation's potent inhibitor. Several efficient sequence-reliant potent inhibitors can be developed in future against the amyloid aggregation for different amyloid peptide by the processing and conformational optimization of CAS.

PMID:33722677 | DOI:10.1016/j.mcn.2021.103612

Antiviral Res. 2021 Mar 12:105062. doi: 10.1016/j.antiviral.2021.105062. Online ahead of print.

ABSTRACT

We recently reported that some clinically approved antifungal drugs are potent inhibitors of human cytomegalovirus (HCMV). Here, we report the broad-spectrum activity against HCMV of isavuconazole (ICZ), a new extended-spectrum triazolic antifungal drug. ICZ inhibited the replication of clinical isolates of HCMV as well as strains resistant to the currently available DNA polymerase inhibitors. The antiviral activity of ICZ against HCMV could be linked to the inhibition of human cytochrome P450 51 (hCYP51), an enzyme whose activity we previously demonstrated to be required for productive HCMV infection. Moreover, time-of-addition studies indicated that ICZ might have additional inhibitory effects during the first phase of HCMV replication. Importantly, ICZ showed synergistic antiviral activity in vitro when administered in combination with different approved anti-HCMV drugs at clinically relevant doses. Together, these results pave the way to possible future clinical studies aimed at evaluating the repurposing potential of ICZ in the treatment of HCMV-associated diseases.

PMID:33722615 | DOI:10.1016/j.antiviral.2021.105062

J Control Release. 2021 Mar 12:S0168-3659(21)00126-7. doi: 10.1016/j.jconrel.2021.03.015. Online ahead of print.

ABSTRACT

Drug repurposing is a promising strategy for identifying new applications for approved drugs. Here, we describe a polymer biomaterial composed of the antiretroviral drug ritonavir derivative (5-methyl-4-oxohexanoic acid ritonavir ester; RD), covalently bound to HPMA copolymer carrier via a pH-sensitive hydrazone bond (P-RD). Apart from being more potent inhibitor of P-glycoprotein in comparison to ritonavir, we found RD to have considerable cytostatic activity in six mice (IC50 ~ 2.3-17.4 μM) and six human (IC50 ~ 4.3-8.7 μM) cancer cell lines, and that RD inhibits the migration and invasiveness of cancer cells in vitro. Importantly, RD inhibits STAT3 phosphorylation in CT26 cells in vitro and in vivo, and expression of the NF-κB p65 subunit, Bcl-2 and Mcl-1 in vitro. RD also dampens chymotrypsin-like and trypsin-like proteasome activity and induces ER stress as documented by induction of PERK phosphorylation and expression of ATF4 and CHOP. P-RD nanomedicine showed powerful antitumor activity in CT26 and B16F10 tumor-bearing mice, which, moreover, synergized with IL-2-based immunotherapy. P-RD proved very promising therapeutic activity also in human FaDu xenografts and negligible toxicity predetermining these nanomedicines as side-effect free nanosystem. The therapeutic potential could be highly increased using the fine-tuned combination with other drugs, i.e. doxorubicin, attached to the same polymer system. Finally, we summarize that described polymer nanomedicines fulfilled all the requirements as potential candidates for deep preclinical investigation.

PMID:33722611 | DOI:10.1016/j.jconrel.2021.03.015

Elife. 2021 Mar 15;10:e63115. doi: 10.7554/eLife.63115. Online ahead of print.

ABSTRACT

Measures of lung function are heritable, and thus, we sought to utilise genetics to propose drug repurposing candidates that could improve respiratory outcomes. Lung function measures were found to be genetically correlated with seven druggable biochemical traits, with further evidence of a causal relationship between increased fasting glucose and diminished lung function. Moreover, we developed polygenic scores for lung function specifically within pathways with known drug targets and investigated their relationship with pulmonary phenotypes and gene expression in independent cohorts to prioritise individuals who may benefit from particular drug repurposing opportunities. A transcriptome-wide association study (TWAS) of lung function was then performed which identified several drug-gene interactions with predicted lung function increasing modes of action. Drugs that regulate blood glucose were uncovered through both the polygenic scoring and TWAS methodologies. In summary, we provided genetic justification for a number of novel drug repurposing opportunities that could improve lung function.

PMID:33720009 | DOI:10.7554/eLife.63115

Curr Drug Res Rev. 2021 Mar 14. doi: 10.2174/2589977513666210315094752. Online ahead of print.

ABSTRACT

BACKGROUND: The novel coronavirus disease 2019 (COVID-19), emerged in Wuhan, China in December 2019 and then spread worldwide rapidly. The records from World Health Organisation (WHO), Centres of Disease Control and Prevention (CDC) and Food and Drug Administration (FDA) backup the fact that no medications have proven to be completely effective for prevention or treatment of SARS-CoV-2. The clinical trials are underway for many repurposed, investigational drugs and vaccine candidates. BioNTech and Pfizer Inc, Moderna, Gamaleya institute and University of Oxford (collaboration with AstraZeneca) announced positive results in the Phase 3 interim analyses of vaccine trials in November 2020. Twelve countries have approved Pfizer- BioNTech COVID-19 vaccine for emergency use, as of December 2020.

OBJECTIVES: The objective was to summarize the repurposed/investigational drugs, their mechanism of action, and rationale for their use in COVID-19 treatment. The article also aimed to summarize the vaccine trials that are currently undergoing across the globe.

METHODS: In order to find the content for review, studies defining COVID-19 chronology, repurposed drugs along with their mode of action and potential vaccine trials were studied and summarized.

RESULTS AND CONCLUSION: The article summarizes potential therapeutic candidates (repurposed and investigational agents) for SARS-CoV-2, their possible mechanism of action and discussion related to their involvement in recent clinical trials. Innovative vaccine platform technologies are also highlighted that are recently being used in the vaccine production pipeline.

PMID:33719950 | DOI:10.2174/2589977513666210315094752