Potential therapeutic targets for combating SARS-CoV-2: Drug repurposing, clinical trials and recent advancements.

Life Sci. 2020 Jun 01;:117883

Authors: Pandey A, Nikam AN, Shreya AB, Mutalik SP, Gopalan D, Kulkarni S, Padya BS, Fernandes G, Mutalik S, Prassl R

Abstract
The present pandemic of SARS-CoV-2 has been a tough task for the whole world to deal with. With the absence of specific drugs or vaccines against SARS-CoV-2, the situation is very difficult to control. Apart from the absence of specific therapies, the lack of knowledge about potential therapeutic targets and individual perception is adding to the complications. The present review describes the novel SARS-CoV-2 structure, surface proteins, asymptomatic and symptomatic transmission in addition to the genotype and phenotype of SARS-CoV-2 along with genetic strains and similarity between SARS, MERS and SARS-CoV-2. Therapeutic strategies such as inhibition of the endocytic pathway and suppressing RNA polymerase activity by metal ions, which could be quite beneficial for controlling COVID-19, are outlined. The drug repurposing for SARS-CoV-2 is discussed in detail along with therapeutic classes such as antivirals, antibiotics, and amino quinolones and their probable role in suppressing SARS-CoV-2 with reference to case studies. The ongoing clinical trials both with respect to drug repurposing and vaccines are summarized along with a brief description. The recent advancements and future perspective of ongoing research for therapy and detection of SARS-CoV-2 are provided. The review, in brief, summarizes epidemiology, therapy and the current scenario for combating SARS-CoV-2.

PMID: 32497632 [PubMed - as supplied by publisher]

Drug Repositioning: Antimalarial Activities of GABA Analogs in Mice Infected with Plasmodium berghei.

Cent Nerv Syst Agents Med Chem. 2020 Jun 04;:

Authors: Ayankunle A, Wakeel O, Kolawole O, Oyekale A, Ojurongbe O, Adeyeba O

Abstract
BACKGROUND: Drug repositioning is becoming popular due to the development of resistance to almost all the recommended antimalarials. Pregabalin and gabapentin are chemical analogs of gamma-aminobutyric acid (GABA) approved for the treatment of epilepsy and neuropathic pain.
OBJECTIVE: This study investigates acute toxicities and antimalarial activities of pregabalin and gabapentin in the murine malarial model.
METHOD: Acute toxicities were assessed using the method of Lorke, while curative activities were assessed by administration of serial doses of pregabalin and gabapentin to Plasmodium berghei infected mice. Pregabalin was further investigated for its prophylactic activity, and curative potential when combined with either artesunate or amodiaquine. All drugs were freshly prepared and administered orally. Thin films were collected, stained, and observed under the microscope for estimation of parasitemia and calculation of percentage chemoinhibition or chemoprevention. In pregabalin -artesunate or -amodiaquine combination aspect of this study, survival day post-infection (SDPI) was recorded, while parasitemia was re-estimated for animals that survived till day 28.
RESULTS: The oral LD50 of gabapentin, as well as pregabalin, was >5,000 mg/kg. Gabapentin at 100 and 200 mg/Kg demonstrated 35.64% and -12.78% chemoinhibition, respectively while pregabalin demonstrated 75.60% and 100.00% chemoinhibition at doses of 12.5 and 25 mg/Kg respectively. Also, pregabalin at individual doses of 25, 50 mg/Kg, and in combination with either artesunate or amodiaquine demonstrated 100.00% chemoinhibition. In its prophylactic study, pregabalin was found to be 100% chemopreventive at individual doses of 12.5 and 25 mg/Kg.
CONCLUSION: Both GABA analogs have antimalarial properties, but pregabalin proved to be more efficacious.

PMID: 32496991 [PubMed - as supplied by publisher]

Pranlukast Antagonizes CD49f and Reduces Stemness in Triple-Negative Breast Cancer Cells.

Drug Des Devel Ther. 2020;14:1799-1811

Authors: Velázquez-Quesada I, Ruiz-Moreno AJ, Casique-Aguirre D, Aguirre-Alvarado C, Cortés-Mendoza F, de la Fuente-Granada M, García-Pérez C, Pérez-Tapia SM, González-Arenas A, Segura-Cabrera A, Velasco-Velázquez MA

Abstract
Introduction: Cancer stem cells (CSCs) drive the initiation, maintenance, and therapy response of breast tumors. CD49f is expressed in breast CSCs and functions in the maintenance of stemness. Thus, blockade of CD49f is a potential therapeutic approach for targeting breast CSCs. In the present study, we aimed to repurpose drugs as CD49f antagonists.
Materials and Methods: We performed consensus molecular docking using a subdomain of CD49f that is critical for heterodimerization and a collection of pharmochemicals clinically tested. Molecular dynamics simulations were employed to further characterize drug-target binding. Using MDA-MB-231 cells, we evaluated the effects of potential CD49f antagonists on 1) cell adhesion to laminin; 2) mammosphere formation; and 3) cell viability. We analyzed the effects of the drug with better CSC-selectivity on the activation of CD49f-downstream signaling by Western blot (WB) and co-immunoprecipitation. Expressions of the stem cell markers CD44 and SOX2 were analyzed by flow cytometry and WB, respectively. Transactivation of SOX2 promoter was evaluated by luciferase reporter assays. Changes in the number of CSCs were assessed by limiting-dilution xenotransplantation.
Results: Pranlukast, a drug used to treat asthma, bound to CD49f in silico and inhibited the adhesion of CD49f+ MDA-MB-231 cells to laminin, indicating that it antagonizes CD49f-containing integrins. Molecular dynamics analysis showed that pranlukast binding induces conformational changes in CD49f that affect its interaction with β1-integrin subunit and constrained the conformational dynamics of the heterodimer. Pranlukast decreased the clonogenicity of breast cancer cells on mammosphere formation assay but had no impact on the viability of bulk tumor cells. Brief exposure of MDA-MB-231 cells to pranlukast altered CD49f-dependent signaling, reducing focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K) activation. Further, pranlukast-treated cells showed decreased CD44 and SOX2 expression, SOX2 promoter transactivation, and in vivo tumorigenicity, supporting that this drug reduces the frequency of CSC.
Conclusion: Our results support the function of pranlukast as a CD49f antagonist that reduces the CSC population in triple-negative breast cancer cells. The pharmacokinetics and toxicology of this drug have already been established, rendering a potential adjuvant therapy for breast cancer patients.

PMID: 32494122 [PubMed - in process]

The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome.

J Clin Med. 2020 Jun 01;9(6):

Authors: Zuliani I, Urbinati C, Valenti D, Quattrini MC, Medici V, Cosentino L, Pietraforte D, Di Domenico F, Perluigi M, Vacca RA, De Filippis B

Abstract
Metformin is the first-line therapy for diabetes, even in children, and a promising attractive candidate for drug repurposing. Mitochondria are emerging as crucial targets of metformin action both in the periphery and in the brain. The present study evaluated whether treatment with metformin may rescue brain mitochondrial alterations and contrast the increased oxidative stress in a validated mouse model of Rett syndrome (RTT), a rare neurologic disorder of monogenic origin characterized by severe behavioral and physiological symptoms. No cure for RTT is available. In fully symptomatic RTT mice (12 months old MeCP2-308 heterozygous female mice), systemic treatment with metformin (100 mg/kg ip for 10 days) normalized the reduced mitochondrial ATP production and ATP levels in the whole-brain, reduced brain oxidative damage, and rescued the increased production of reactive oxidizing species in blood. A 10-day long treatment with metformin also boosted pathways related to mitochondrial biogenesis and antioxidant defense in the brain of metformin-treated RTT mice. This treatment regimen did not improve general health status and motor dysfunction in RTT mice at an advanced stage of the disease. Present results provide evidence that systemic treatment with metformin may represent a novel, repurposable therapeutic strategy for RTT.

PMID: 32492904 [PubMed]

H1-antihistamines as antischistosomal drugs: in vitro and in vivo studies.

Parasit Vectors. 2020 Jun 01;13(1):278

Authors: Xavier RP, Mengarda AC, Silva MP, Roquini DB, Salvadori MC, Teixeira FS, Pinto PL, Morais TR, Ferreira LLG, Andricopulo AD, de Moraes J

Abstract
BACKGROUND: Schistosomiasis is a socioeconomically devastating parasitic infection afflicting hundreds of millions of people and animals worldwide. It is the most important helminth infection, and its treatment relies solely on the drug praziquantel. Oral H1-antihistamines are available worldwide, and these agents are among the most widely used of all medications in children and adults. Given the importance of the drug repositioning strategy, we evaluated the antischistosomal properties of the H1-antihistamine drugs commonly used in clinical practices.
METHODS: Twenty-one antihistamine drugs were initially screened against adult schistosomes ex vivo. Subsequently, we investigated the anthelmintic properties of these antihistamines in a murine model of schistosomiasis for both early and chronic S. mansoni infections at oral dosages of 400 mg/kg single dose or 100 mg/kg daily for five consecutive days. We also demonstrated and described the ability of three antihistamines to induce tegumental damage in schistosomes through the use of scanning electron microscopy.
RESULTS: From phenotypic screening, we found that desloratadine, rupatadine, promethazine, and cinnarizine kill adult S. mansoni in vitro at low concentrations (5-15 µM). These results were further supported by scanning electron microscopy analysis. In an animal model, rupatadine and cinnarizine revealed moderate worm burden reductions in mice harboring either early or chronic S. mansoni infection. Egg production, a key mechanism for both transmission and pathogenesis, was also markedly inhibited by rupatadine and cinnarizine, and a significant reduction in hepatomegaly and splenomegaly was recorded. Although less effective, desloratadine also revealed significant activity against the adult and juvenile parasites.
CONCLUSIONS: Although the worm burden reductions achieved are all only moderate, comparatively, treatment with any of the three antihistamines is more effective in early infection than praziquantel. On the other hand, the clinical use of H1-antihistamines for the treatment of schistosomiasis is highly unlikely.

PMID: 32487175 [PubMed - in process]

Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition.

Int J Mol Sci. 2020 May 27;21(11):

Authors: Gimeno A, Mestres-Truyol J, Ojeda-Montes MJ, Macip G, Saldivar-Espinoza B, Cereto-Massagué A, Pujadas G, Garcia-Vallvé S

Abstract
Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread worldwide, the scientific community has been under pressure to react and make progress in the development of an effective treatment against the virus responsible for the disease. Here, we implement an original virtual screening (VS) protocol for repositioning approved drugs in order to predict which of them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given its essential role in the virus' replication. Two different libraries of approved drugs were docked against the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses. In this way, we took advantage of the three sampling algorithms to generate hypothetic binding modes without relying on a single scoring function to rank the results. Seven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel, Carprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen and Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show 3.97 and 11.90% M-pro inhibition at 50 µM, respectively.

PMID: 32471205 [PubMed - indexed for MEDLINE]

Old active ingredients in new medicinal products: is the regulatory path coherent with patients' expectations?

Drug Discov Today. 2020 May 30;:

Authors: Minghetti P, Musazzi UM, Casiraghi A, Rocco P

Abstract
The rising costs of new medicinal products are a challenge to the economic sustainability of national healthcare systems in ensuring patients' access to therapies. European Union (EU) and US legislators have provided regulatory pathways aimed at simplifying Marketing Authorization (MA) applications for new medicinal products in cases when safety and efficacy profiles can be derived from the data of already-marketed products. In this review, we discuss the different regulatory pathways towards the MA of new medicinal products containing old drug substances and intended to improve the therapeutic value of a treatment, to obtain a new therapeutic indication (drug repositioning), or to ensure the same therapeutic value of a reference product at lower costs.

PMID: 32485225 [PubMed - as supplied by publisher]

Scoring functions for drug-effect similarity.

Brief Bioinform. 2020 Jun 02;:

Authors: Struckmann S, Ernst M, Fischer S, Mah N, Fuellen G, Möller S

Abstract
MOTIVATION: The difficulty to find new drugs and bring them to the market has led to an increased interest to find new applications for known compounds. Biological samples from many disease contexts have been extensively profiled by transcriptomics, and, intuitively, this motivates to search for compounds with a reversing effect on the expression of characteristic disease genes. However, disease effects may be cell line-specific and also depend on other factors, such as genetics and environment. Transcription profile changes between healthy and diseased cells relate in complex ways to profile changes gathered from cell lines upon stimulation with a drug. Despite these differences, we expect that there will be some similarity in the gene regulatory networks at play in both situations. The challenge is to match transcriptomes for both diseases and drugs alike, even though the exact molecular pathology/pharmacogenomics may not be known.
RESULTS: We substitute the challenge to match a drug effect to a disease effect with the challenge to match a drug effect to the effect of the same drug at another concentration or in another cell line. This is welldefined, reproducible in vitro and in silico and extendable with external data. Based on the Connectivity Map (CMap) dataset, we combined 26 different similarity scores with six different heuristics to reduce the number of genes in the model. Such gene filters may also utilize external knowledge e.g. from biological networks. We found that no similarity score always outperforms all others for all drugs, but the Pearson correlation finds the same drug with the highest reliability. Results are improved by filtering for highly expressed genes and to a lesser degree for genes with large fold changes. Also a network-based reduction of contributing transcripts was beneficial, here implemented by the FocusHeuristics. We found no drop in prediction accuracy when reducing the whole transcriptome to the set of 1000 landmark genes of the CMap's successor project Library of Integrated Network-based Cellular Signatures. All source code to re-analyze and extend the CMap data, the source code of heuristics, filters and their evaluation are available to propel the development of new methods for drug repurposing.
AVAILABILITY: https://bitbucket.org/ibima/moldrugeffectsdb.
CONTACT: steffen.moeller@uni-rostock.de.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Briefings in Bioinformatics online.

PMID: 32484516 [PubMed - as supplied by publisher]

A computational drug repositioning method applied to rare diseases: Adrenocortical carcinoma.

Sci Rep. 2020 Jun 01;10(1):8846

Authors: Lotfi Shahreza M, Ghadiri N, Green JR

Abstract
Rare or orphan diseases affect only small populations, thereby limiting the economic incentive for the drug development process, often resulting in a lack of progress towards treatment. Drug repositioning is a promising approach in these cases, due to its low cost. In this approach, one attempts to identify new purposes for existing drugs that have already been developed and approved for use. By applying the process of drug repositioning to identify novel treatments for rare diseases, we can overcome the lack of economic incentives and make concrete progress towards new therapies. Adrenocortical Carcinoma (ACC) is a rare disease with no practical and definitive therapeutic approach. We apply Heter-LP, a new method of drug repositioning, to suggest novel therapeutic avenues for ACC. Our analysis identifies innovative putative drug-disease, drug-target, and disease-target relationships for ACC, which include Cosyntropin (drug) and DHCR7, IGF1R, MC1R, MAP3K3, TOP2A (protein targets). When results are analyzed using all available information, a number of novel predicted associations related to ACC appear to be valid according to current knowledge. We expect the predicted relations will be useful for drug repositioning in ACC since the resulting ranked lists of drugs and protein targets can be used to expedite the necessary clinical processes.

PMID: 32483162 [PubMed - in process]

Considerations for Drug Interactions on QTc Interval in Exploratory COVID-19 Treatment.

J Am Coll Cardiol. 2020 05 26;75(20):2623-2624

Authors: Roden DM, Harrington RA, Poppas A, Russo AM

PMID: 32283123 [PubMed - indexed for MEDLINE]

Predicting The Effects of Chemical-Protein Interactions On Proteins Using Tensor Factorisation.

AMIA Jt Summits Transl Sci Proc. 2020;2020:430-439

Authors: Mohamed SK, Nounu A

Abstract
Understanding the different effects of chemical substances on human proteins is fundamental for designing new drugs. It is also important for elucidating the different mechanisms of action of drugs that can cause side-effects. In this context, computational methods for predicting chemical-protein interactions can provide valuable insights on the relation between therapeutic chemical substances and proteins. Their predictions therefore can help in multiple tasks such as drug repurposing, identifying new drug side-effects, etc. Despite their useful predictions, these methods are unable to predict the different implications - such as change in protein expression, abundance, etc, - of chemical - protein interactions. Therefore, In this work, we study the modelling of chemical-protein interactions' effects on proteins activity using computational approaches. We hereby propose using 3D tensors to model chemicals, their target proteins and the effects associated to their interactions. We then use multi-part embedding tensor factorisation to predict the different effects of chemicals on human proteins. We assess the predictive accuracy of our proposed method using a benchmark dataset that we built. We then show by computational experimental evaluation that our approach outperforms other tensor factorisation methods in the task of predicting effects of chemicals on human proteins.

PMID: 32477664 [PubMed]

Using Entity Metrics to Understand Drug Repurposing.

AMIA Jt Summits Transl Sci Proc. 2020;2020:377-382

Authors: Li X, Ding Y, Lu W

Abstract
Understanding the process of drug repurposing is critically significant for drug development. In this paper, we employ extracted bio-entities to detect the features of different phases in drug repurposing. We proposed a transparent and easy entitymetric indicator for bio-entities, i.e., Popularity Index, to quantify and visualize the dynamic changes in academic interests of bio-entities. By taking aspirin as an example, the results display specific profiles of drug repurposing and the evolution of bio-entities in the different phases of drug research, which would potentially be valuable for pharmaceutical companies and scholars to successfully discover and repurpose drugs.

PMID: 32477658 [PubMed]

Longitudinal [18F]FB-IL-2 PET Imaging to Assess the Immunopathogenicity of O'nyong-nyong Virus Infection.

Front Immunol. 2020;11:894

Authors: Chan YH, Teo TH, Torres-Ruesta A, Hartimath SV, Chee RS, Khanapur S, Yong FF, Ramasamy B, Cheng P, Rajarethinam R, Robins EG, Goggi JL, Lum FM, Carissimo G, Rénia L, Ng LFP

Abstract
O'nyong-nyong virus (ONNV) is an arthritogenic alphavirus that caused two large epidemics in 1959 and 1996, affecting millions of people in Africa. More recently, sero-surveillance of healthy blood donors conducted in 2019 revealed high rates of unreported ONNV infection in Uganda. Due to similar clinical symptoms with other endemic mosquito-borne pathogens in the region, including chikungunya virus, dengue virus and malaria, ONNV infections are often un- or misdiagnosed. Elucidating the immunopathogenic factors of this re-emerging arbovirus is critical with the expanding geographic distribution of competent vectors. This study reports the establishment of an immune competent C57BL6/J mouse model to mechanistically characterize ONNV infection and assess potential treatment efficacy. This mouse model successfully recapitulated arthralgia and viremia profiles seen in ONNV patients. Furthermore, longitudinal in-vivo PET imaging with [18F]FB-IL-2 (CD25+CD4+ binding probe) and histopathological assessment in this model demonstrated the pathogenic role of CD4+ T cells in driving joint pathology. Concordantly, in vivo CD4+ T cell depletion, or suppression with fingolimod, an FDA-approved immunomodulating drug, abrogated CD4+ T cell-mediated disease. This study demonstrates the importance of this immune competent ONNV model for future studies on factors influencing disease pathogenesis, which could shape the discovery of novel therapeutic strategies for arthritogenic alphaviruses.

PMID: 32477364 [PubMed - in process]

Repurposed Analog of GLP-1 Ameliorates Hyperglycemia in Type 1 Diabetic Mice Through Pancreatic Cell Reprogramming.

Front Endocrinol (Lausanne). 2020;11:258

Authors: Villalba A, Rodriguez-Fernandez S, Perna-Barrull D, Ampudia RM, Gomez-Muñoz L, Pujol-Autonell I, Aguilera E, Coma M, Cano-Sarabia M, Vázquez F, Verdaguer J, Vives-Pi M

Abstract
Type 1 diabetes is an autoimmune disease caused by the destruction of the insulin-producing β-cells. An ideal immunotherapy should combine the blockade of the autoimmune response with the recovery of functional target cell mass. With the aim to develop new therapies for type 1 diabetes that could contribute to β-cell mass restoration, a drug repositioning analysis based on systems biology was performed to identify the β-cell regenerative potential of commercially available compounds. Drug repositioning is a strategy used for identifying new uses for approved drugs that are outside the scope of the medical indication. A list of 28 non-synonymous repurposed drug candidates was obtained, and 16 were selected as diabetes mellitus type 1 treatment candidates regarding pancreatic β-cell regeneration. Drugs with poor safety profile were further filtered out. Lastly, we selected liraglutide for its predictive efficacy values for neogenesis, transdifferentiation of α-cells, and/or replication of pre-existing β-cells. Liraglutide is an analog of glucagon-like peptide-1, a drug used in patients with type 2 diabetes. Liraglutide was tested in immunodeficient NOD-Scid IL2rg -/- (NSG) mice with type 1 diabetes. Liraglutide significantly improved the blood glucose levels in diabetic NSG mice. During the treatment, a significant increase in β-cell mass was observed due to a boost in β-cell number. Both parameters were reduced after withdrawal. Interestingly, islet bihormonal glucagon+insulin+ cells and insulin+ ductal cells arose during treatment. In vitro experiments showed an increase of insulin and glucagon gene expression in islets cultured with liraglutide in normoglycemia conditions. These results point to β-cell replacement, including transdifferentiation and neogenesis, as aiding factors and support the role of liraglutide in β-cell mass restoration in type 1 diabetes. Understanding the mechanism of action of this drug could have potential clinical relevance in this autoimmune disease.

PMID: 32477262 [PubMed - in process]

An Old Drug for a New Indication: Repurposing Fenfluramine From an Anorexigen to an Antiepileptic Drug.

Clin Pharmacol Ther. 2019 11;106(5):929-932

Authors: Schoonjans AS, Ceulemans B

PMID: 31116409 [PubMed - indexed for MEDLINE]

Antitumor effects of ivermectin at clinically feasible concentrations support its clinical development as a repositioned cancer drug.

Cancer Chemother Pharmacol. 2020 May 30;:

Authors: Juarez M, Schcolnik-Cabrera A, Dominguez-Gomez G, Chavez-Blanco A, Diaz-Chavez J, Duenas-Gonzalez A

Abstract
PURPOSE: Ivermectin is an antiparasitic drug that exhibits antitumor effects in preclinical studies, and as such is currently being repositioned for cancer treatment. However, divergences exist regarding its employed doses in preclinical works. Therefore, the aim of this study was to determine whether the antitumor effects of ivermectin are observable at clinically feasible drug concentrations.
METHODS: Twenty-eight malignant cell lines were treated with 5 μM ivermectin. Cell viability, clonogenicity, cell cycle, cell death and pharmacological interaction with common cytotoxic drugs were assessed, as well as the consequences of its use on stem cell-enriched populations. The antitumor in vivo effects of ivermectin were also evaluated.
RESULTS: The breast MDA-MB-231, MDA-MB-468, and MCF-7, and the ovarian SKOV-3, were the most sensitive cancer cell lines to ivermectin. Conversely, the prostate cancer cell line DU145 was the most resistant to its use. In the most sensitive cells, ivermectin induced cell cycle arrest at G0-G1 phase, with modulation of proteins associated with cell cycle control. Furthermore, ivermectin was synergistic with docetaxel, cyclophosphamide and tamoxifen. Ivermectin reduced both cell viability and colony formation capacity in the stem cell-enriched population as compared with the parental one. Finally, in tumor-bearing mice ivermectin successfully reduced both tumor size and weight.
CONCLUSION: Our results on the antitumor effects of ivermectin support its clinical testing.

PMID: 32474842 [PubMed - as supplied by publisher]

Comprehensive analysis of drugs to treat SARS‑CoV‑2 infection: Mechanistic insights into current COVID‑19 therapies (Review).

Int J Mol Med. 2020 May 18;:

Authors: Nitulescu GM, Paunescu H, Moschos SA, Petrakis D, Nitulescu G, Ion GND, Spandidos DA, Nikolouzakis TK, Drakoulis N, Tsatsakis A

Abstract
The major impact produced by the severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) focused many researchers attention to find treatments that can suppress transmission or ameliorate the disease. Despite the very fast and large flow of scientific data on possible treatment solutions, none have yet demonstrated unequivocal clinical utility against coronavirus disease 2019 (COVID‑19). This work represents an exhaustive and critical review of all available data on potential treatments for COVID‑19, highlighting their mechanistic characteristics and the strategy development rationale. Drug repurposing, also known as drug repositioning, and target based methods are the most used strategies to advance therapeutic solutions into clinical practice. Current in silico, in vitro and in vivo evidence regarding proposed treatments are summarized providing strong support for future research efforts.

PMID: 32468014 [PubMed - as supplied by publisher]

High-throughput screening of clinically approved drugs that prime nonviral gene delivery to human Mesenchymal stem cells.

J Biol Eng. 2020;14:16

Authors: Kozisek T, Hamann A, Nguyen A, Miller M, Plautz S, Pannier AK

Abstract
Background: Human mesenchymal stem cells (hMSCs) are intensely researched for applications in cell therapeutics due to their unique properties, however, intrinsic therapeutic properties of hMSCs could be enhanced by genetic modification. Viral transduction is efficient, but suffers from safety issues. Conversely, nonviral gene delivery, while safer compared to viral, suffers from inefficiency and cytotoxicity, especially in hMSCs. To address the shortcomings of nonviral gene delivery to hMSCs, our lab has previously demonstrated that pharmacological 'priming' of hMSCs with the glucocorticoid dexamethasone can significantly increase transfection in hMSCs by modulating transfection-induced cytotoxicity. This work seeks to establish a library of transfection priming compounds for hMSCs by screening 707 FDA-approved drugs, belonging to diverse drug classes, from the NIH Clinical Collection at four concentrations for their ability to modulate nonviral gene delivery to adipose-derived hMSCs from two human donors.
Results: Microscope images of cells transfected with a fluorescent transgene were analyzed in order to identify compounds that significantly affected hMSC transfection without significant toxicity. Compound classes that increased transfection across both donors included glucocorticoids, antibiotics, and antihypertensives. Notably, clobetasol propionate, a glucocorticoid, increased transgene production 18-fold over unprimed transfection. Furthermore, compound classes that decreased transfection across both donors included flavonoids, antibiotics, and antihypertensives, with the flavonoid epigallocatechin gallate decreasing transgene production - 41-fold compared to unprimed transfection.
Conclusions: Our screen of the NCC is the first high-throughput and drug-repurposing approach to identify nonviral gene delivery priming compounds in two donors of hMSCs. Priming compounds and classes identified in this screen suggest that modulation of proliferation, mitochondrial function, and apoptosis is vital for enhancing nonviral gene delivery to hMSCs.

PMID: 32467728 [PubMed]

Erdafitinib Resensitizes ABCB1-Overexpressing Multidrug-Resistant Cancer Cells to Cytotoxic Anticancer Drugs.

Cancers (Basel). 2020 May 26;12(6):

Authors: Wu CP, Hung TH, Hsiao SH, Huang YH, Hung LC, Yu YJ, Chang YT, Wang SP, Wu YS

Abstract
The development of multidrug resistance (MDR) in cancer patients, which is often associated with the overexpression of ABCB1 (MDR1, P-glycoprotein) in cancer cells, remains a significant problem in cancer chemotherapy. ABCB1 is one of the major adenosine triphosphate (ATP)-binding cassette (ABC) transporters that can actively efflux a range of anticancer drugs out of cancer cells, causing MDR. Given the lack of Food and Drug Administration (FDA)-approved treatment for multidrug-resistant cancers, we explored the prospect of repurposing erdafitinib, the first fibroblast growth factor receptor (FGFR) kinase inhibitor approved by the FDA, to reverse MDR mediated by ABCB1. We discovered that by reducing the function of ABCB1, erdafitinib significantly resensitized ABCB1-overexpressing multidrug-resistant cancer cells to therapeutic drugs at sub-toxic concentrations. Results of erdafitinib-stimulated ABCB1 ATPase activity and in silico docking analysis of erdafitinib binding to the substrate-binding pocket of ABCB1 further support the interaction between erdafitinib and ABCB1. Moreover, our data suggest that ABCB1 is not a major mechanism of resistance to erdafitinib in cancer cells. In conclusion, we revealed an additional action of erdafitinib as a potential treatment option for multidrug-resistant cancers, which should be evaluated in future drug combination trials.

PMID: 32466597 [PubMed]

COVID-19: an unexpected indication for anti-rheumatic therapies?

Rheumatology (Oxford). 2020 06 01;59(6):1200-1203

Authors: Lucchino B, Di Franco M, Conti F

PMID: 32374874 [PubMed - indexed for MEDLINE]