Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease.

Life Sci. 2020 Jun 15;251:117627

Authors: Kandeel M, Al-Nazawi M

Abstract
AIMS: In December 2019, the Coronavirus disease-2019 (COVID-19) virus has emerged in Wuhan, China. In this research, the first resolved COVID-19 crystal structure (main protease) was targeted in a virtual screening study by of FDA approved drugs dataset. In addition, a knowledge gap in relations of COVID-19 with the previously known fatal Coronaviruses (CoVs) epidemics, SARS and MERS CoVs, was covered by investigation of sequence statistics and phylogenetics.
MATERIALS AND METHODS: Molecular modeling, virtual screening, docking, sequence comparison statistics and phylogenetics of the COVID-19 main protease were investigated.
KEY FINDINGS: COVID-19 Mpro formed a phylogenetic group with SARS CoV that was distant from MERS CoV. The identity% was 96.061 and 51.61 for COVID-19/SARS and COVID-19/MERS CoV sequence comparisons, respectively. The top 20 drugs in the virtual screening studies comprised a broad-spectrum antiviral (ribavirin), anti-hepatitis B virus (telbivudine), two vitamins (vitamin B12 and nicotinamide) and other miscellaneous systemically acting drugs. Of special interest, ribavirin had been used in treating cases of SARS CoV.
SIGNIFICANCE: The present study provided a comprehensive targeting of the first resolved COVID+19 structure of Mpro and found a suitable save drugs for repurposing against the viral Mpro. Ribavirin, telbivudine, vitamin B12 and nicotinamide can be combined and used for COVID treatment. This initiative relocates already marketed and approved safe drugs for potential use in COVID-treatment.

PMID: 32251634 [PubMed - indexed for MEDLINE]

SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: An in silico perspective.

J Biomol Struct Dyn. 2020 Apr 26;:1-15

Authors: Elfiky AA

Abstract
New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19.

PMID: 32338164 [PubMed - as supplied by publisher]

Drug repurposing in Raynaud's phenomenon through adverse event signature matching in the WHO pharmacovigilance database.

Br J Clin Pharmacol. 2020 Apr 26;:

Authors: Putkaradze Z, Roustit M, Cracowski JL, Khouri C

Abstract
OBJECTIVE: Several pharmacological treatments are actually recommended for Raynaud's phenomenon (RP) secondary to systemic sclerosis, but they only have modest efficacy. A way to efficiently identify new drugs is drug repurposing, which can be based on signature matching. The signature could be derived from chemical structures, pharmacological affinity profile or adverse event profile. We propose to use the WHO pharmacovigilance database to generate repositioning hypotheses for treatments of RP through adverse event signature matching.
METHODS: We first screened all drugs associated with at least one case of erythromelalgia, an adverse effect opposite to RP. In parallel, in order to define the adverse event signature of drugs recommended in secondary RP from the WHO pharmacovigilance database, we selected the 14 most representative adverse drug reaction (ADR). Lastly, we performed a hierarchical cluster analysis to identify drugs with similar ADR signature to vasodilatory drugs used in RP.
RESULTS: A total of 179 drugs were associated with erythromelalgia; they were related to 860,334 adverse events representative of RP drugs in the WHO pharmacovigilance database. Hierarchical cluster analysis allowed identification of 6 clusters. The most stable cluster contained 7 drugs, among which 5 are recommended in secondary RP, or pertain to the same drug class: epoprostenol, nifedipine, nicardipine, lacidipine, and israpidine. The two remaining drugs were alemtuzumab and fumaric acid.
CONCLUSION: Our ADR signature matching approach suggests that alemtuzumab and fumaric acid could be effective treatments of secondary RP. The latter is currently being investigated as a treatment of pulmonary hypertension in systemic sclerosis.

PMID: 32337731 [PubMed - as supplied by publisher]

Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling.

Cancer Lett. 2019 08 10;457:86-97

Authors: Lin CC, Suen KM, Stainthorp A, Wieteska L, Biggs GS, Leitão A, Montanari CA, Ladbury JE

Abstract
Receptor tyrosine kinase (RTK)-mediated hyperactivation of the MAPK/Erk pathway is responsible for a large number of pathogenic outcomes including many cancers. Considerable effort has been directed at targeting this pathway with varying degrees of long term therapeutic success. Under non-stimulated conditions Erk is bound to the adaptor protein Shc preventing aberrant signalling by sequestering Erk from activation by Mek. Activated RTK recruits Shc, via its phosphotyrosine binding (PTB) domain (ShcPTB), precipitating the release of Erk to engage in a signalling response. Here we describe a novel approach to inhibition of MAP kinase signal transduction through attempting to preserve the Shc-Erk complex under conditions of activated receptor. A library of existing drug molecules was computationally screened for hits that would bind to the ShcPTB and block its interaction with the RTKs EGFR and ErbB2. The primary hit from the screen was indomethacin, a non-steroidal anti-inflammatory drug. Validation of this molecule in vitro and in cellular efficacy studies in cancer cells provides proof of principle of the approach to pathway down-regulation and a potential optimizable lead compound.

PMID: 31100409 [PubMed - indexed for MEDLINE]

Current pharmacological treatments for COVID-19: what's next?

Br J Pharmacol. 2020 Apr 24;:

Authors: Scavone C, Brusco S, Bertini M, Sportiello L, Rafaniello C, Zoccoli A, Berrino L, Racagni G, Rossi F, Capuano A

Abstract
Starting from December 2019 the novel SARS-Cov-2 has spread all over the world, being recognized as the causing agent of COVID-19. Since nowadays no specific drug therapies neither vaccines are available for the treatment of COVID-19, drug repositioning may offer a strategy to efficiently control the clinical course of the disease and the spread of the outbreak. In this paper we aim to describe the main pharmacological properties, including data on mechanism of action, safety concerns and drug-drug interactions, of drugs currently administered in patients with COVID-19, focusing on antivirals and drugs with immune-modulatory and/or anti-inflammatory properties. Where available, data from clinical trials involving patients with COVID-19 were reported. Several studies have been registered worldwide and a number of drugs were repurposed to face the new health emergency of COVID-19. For many of these drugs, including lopinavir/ritonavir, remdesivir, favipiravir and tocilizumab, preliminary clinical trials seem to support their benefit in improving patients' clinical conditions. However, adequate clinical trials are necessary to reach any firm conclusion on the efficacy and safety profiles of these compounds. Even though drug repurposing is necessary, it requires caution. Too many drugs that are currently tested in patients with COVID-19 have peculiar safety profiles. In conclusion, while waiting for the development of effective preventive measures, such as vaccines, many clinical trials on drugs belonging to different therapeutic classes are currently underway. It is conceivable that very soon their results will help us in defining the best way to treat COVID-19 and reducing its symptoms and complications.

PMID: 32329520 [PubMed - as supplied by publisher]

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis.

Int J Mol Sci. 2020 Apr 19;21(8):

Authors: Shi Q, Pei F, Silverman GA, Pak SC, Perlmutter DH, Liu B, Bahar I

Abstract
Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here, we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g., artenimol and olanzapine acting as activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

PMID: 32325894 [PubMed - in process]

COVID-19 Drug Discovery Using Intensive Approaches.

Int J Mol Sci. 2020 Apr 18;21(8):

Authors: Asai A, Konno M, Ozaki M, Otsuka C, Vecchione A, Arai T, Kitagawa T, Ofusa K, Yabumoto M, Hirotsu T, Taniguchi M, Eguchi H, Doki Y, Ishii H

Abstract
Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.

PMID: 32325767 [PubMed - in process]

[CoViD-19: we knew everything but we didn't understand anything.]

Recenti Prog Med. 2020 04;111(4):181-182

Authors: Addis A

Abstract
The CoViD-19 and its consequences could perhaps have been foreseen. Above all, this pandemic force us to review what is essential and really necessary in term of priorities and regulatory process for clinical pharmacological research. It is evident, among other things, the difficulty to deal with therapeutic uncertainties.Not proven specific therapies are available for the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2, the cause of CoViD-19), other than supportive care. However, several clinical centres decided to use off label drugs as a standard of care in the absence of efficacy and safety data. The national regulatory body (AIFA) has set up a process in a short time to transparently govern the approval of new trials and to regulate the use of medicines that are not indicated. In this context, the communication of risk associated with experimental therapies was also very important. The lessons we will learn from this emergency may result crucial in redesigning a better way of conducting clinical trials and information on drugs.

PMID: 32319433 [PubMed - indexed for MEDLINE]

High-throughput analysis identifying drugs that reduce oxidative and ER stress in human coronary artery endothelial cells.

Eur J Pharmacol. 2020 Apr 20;:173119

Authors: Haas MJ, Feng V, Gonzales K, Onstead-Haas L, Mooradian AD

Abstract
Endoplasmic reticulum (ER) stress as well as oxidative stress have been shown to play important roles in metabolic and cardiovascular disease, and drugs that counteract the effects of ER and oxidative stresses maybe clinically useful. To identify novel compounds that ameliorate ER and oxidative stresses, we screened two drug libraries purchased from Evotec, San Francisco, CA; the NIH clinical collection 1 (446 compounds) and the NIH clinical collection 2 (281 compounds). Human coronary artery endothelial cells (HCAEC) were tested for ER and oxidative stress. ER stress was measured with an ER stress-sensitive secreted alkaline phosphatase (SAP) assay. The cells were transfected with the plasmid pSAP2. Control, expressing a heat-resistant form of SAP, and treated with the ER stress inducer tunicamycin in the presence or absence of each of the various compounds for 24-h, at which time SAP activity was measured. Compounds exhibiting significant increases in SAP activity (41 compounds out of a total of 727 tested; 5.6%) were then assayed for their ability to suppress superoxide (SO) anion generation in cells treated with 27.5 mM dextrose. SO generation was measured using the superoxide-reactive probe 2-methyl-6-(4-methoxyphenyl)-3,7-dihydroimidazo[1,2-A]pyrazin-3-one hydrochloride chemiluminescence. Of the 41 compounds identified as ER stress reducers, only 33 (80.5%) suppressed dextrose-induced SO anion generation. Interestingly, 51% of the compounds found to be dual-stress modifiers consisted of cardioprotective drugs, including statins, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors as well as β-blockers. Future studies to validate the clinical effectiveness of these agents remain to be performed in pre-clinical and clinical trials.

PMID: 32325145 [PubMed - as supplied by publisher]

Neonatal therapy with clenbuterol and salmeterol restores spinogenesis and dendritic complexity in the dentate gyrus of the Ts65Dn model of Down syndrome.

Neurobiol Dis. 2020 Apr 20;:104874

Authors: Emili M, Stagni F, Salvalai ME, Uguagliati B, Giacomini A, Albach C, Potier MC, Grilli M, Bartesaghi R, Guidi S

Abstract
Down syndrome (DS), a neurodevelopmental disorder caused by triplication of chromosome 21, is characterized by intellectual disability. In DS, defective neurogenesis causes an overall reduction in the number of neurons populating the brain and defective neuron maturation causes dendritic hypotrophy and reduction in the density of dendritic spines. No effective therapy currently exists for the improvement of brain development in individuals with DS. Drug repurposing is a strategy for identifying new medical use for approved drugs. A drug screening campaign showed that the β2-adrenergic receptor (β2-AR) agonists clenbuterol hydrochloride (CLEN) and salmeterol xinafoate (SALM) increase the proliferation rate of neural progenitor cells from the Ts65Dn model of DS. The goal of the current study was to establish their efficacy in vivo, in the Ts65Dn model. We found that, at variance with the in vitro experiments, treatment with CLEN or SALM did not restore neurogenesis in the hippocampus of Ts65Dn mice treated during the postnatal (P) period P3-P15. In Ts65Dn mice treated with CLEN or SALM, however, dendritic spine density and dendritic arborization of the hippocampal granule cells were restored and the lowest dose tested here (0.01 mg/kg/day) was sufficient to elicit these effects. CLEN and SALM are used in children as therapy for asthma and, importantly, they pass the blood-brain barrier. Our study suggests that treatment with these β2-AR agonists may be a therapy of choice in order to correct dendritic development in DS but is not suitable to rescue neurogenesis.

PMID: 32325119 [PubMed - as supplied by publisher]

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease.

Acta Pharm Sin B. 2020 Apr;10(4):646-666

Authors: Li X, Lu J, Xu Y, Wang J, Qiu X, Fan L, Li B, Liu W, Mao F, Zhu J, Shen X, Li J

Abstract
Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.

PMID: 32322468 [PubMed]

COVID-19, Chloroquine Repurposing, and Cardiac Safety Concern: Chirality Might Help.

Molecules. 2020 Apr 16;25(8):

Authors: Lentini G, Cavalluzzi MM, Habtemariam S

Abstract
The desperate need to find drugs for COVID-19 has indicated repurposing strategies as our quickest way to obtain efficacious medicines. One of the options under investigation is the old antimalarial drug, chloroquine, and its analog, hydroxychloroquine. Developed as synthetic succedanea of cinchona alkaloids, these chiral antimalarials are currently in use as the racemate. Besides the ethical concern related to accelerated large-scale clinical trials of drugs with unproven efficacy, the known potential detrimental cardiac effects of these drugs should also be considered. In principle, the safety profile might be ameliorated by using chloroquine/hydroxychloroquine single enantiomers in place of the racemate.

PMID: 32316270 [PubMed - indexed for MEDLINE]

Repurposing Ponatinib as a Potent Agent against KIT Mutant Melanomas.

Theranostics. 2019;9(7):1952-1964

Authors: Han Y, Gu Z, Wu J, Huang X, Zhou R, Shi C, Tao W, Wang L, Wang Y, Zhou G, Li J, Zhang Z, Sun S

Abstract
Rationale: Mutations in KIT, a major cancer driver gene, are now considered as important drug targets for the treatment of melanomas arising from mucosal and acral tissues and from chronically sun-damaged sites. At present, imatinib is the only targeted drug for KIT-mutation-bearing melanomas that is recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice guidelines. Patients with KIT mutations, however, are either insensitive or rapidly progress to imatinib insensitivity, which restricts its clinical use. Thus, effective inhibitors of KIT-mutation-bearing melanomas are urgently needed. Methods: A cohort of patient-derived tumor xenograft (PDX) models and corresponding PDX-derived cells (PDCs) from patients with melanomas harboring KIT mutations (KIT V560D, KIT K642E and KIT D816V) were established, characterized, and then used to test the in vitro and, subsequently, in vivo inhibitory effects of a panel of known KIT inhibitors. Results: Ponatinib was more potent than imatinib against cells bearing KIT mutations. In vivo drug efficacy evaluation experiments showed that ponatinib treatment caused much stronger inhibition of KIT-mutation-bearing melanomas than did imatinib. Mechanistically, molecular dynamics (MD) simulations revealed a plausible atomic-level explanation for the observation that ponatinib has a higher affinity for the KIT D816V mutant protein than does imatinib. Conclusions: Our study of KIT-mutation-and KIT WT-bearing melanomas demonstrates that ponatinib is a far more potent inhibitor than is imatinib for KIT-mutation-bearing melanomas and thus underscores that ponatinib should be given priority consideration for the design of precision treatments for melanoma patients triaged to have KIT mutations. Moreover, our work provides a rationale for undertaking clinical trials to examine the repurposing of ponatinib, which is already approved for use in leukemia, for use in treating a large subset of melanoma patients.

PMID: 31037149 [PubMed - indexed for MEDLINE]

Repurposing of respiratory drug theophylline against Candida albicans: Mechanistic insights unveil alterations in membrane properties and metabolic fitness.

J Appl Microbiol. 2020 Apr 22;:

Authors: Singh S, Fatima Z, Ahmad K, Hameed S

Abstract
AIMS: Drug repurposing is an attractive chemotherapeutic strategy that serves to make up for the inadequacy of current antifungal drugs. The present study aims to repurpose theophylline (THP) against Candida albicans. THP is a methylxanthine derived from cocoa beans and tea extracts, generally used as the first-line drug for asthma and other respiratory disorders.
METHODS AND RESULTS: We investigated the antifungal activity of THP against C. albicans and non-albicans species. Mechanistic insights revealed that THP induces membrane damage. Enhanced ionic disturbances, depleted ergosterol levels with the concomitant rise in membrane fluidity due to elevated flippase activity confirmed the membrane damaging effect. THP impeded the metabolic adaptability of C. albicans by inhibiting malate synthase and isocitrate lyase enzymes of the glyoxylate cycle. In vivo efficacy of THP was depicted by increased survival of C. albicans infected Caenorhabditis elegans model.
CONCLUSIONS: This study elucidates the antifungal potential of THP with mechanistic insights.
SIGNIFICANCE AND IMPACT OF STUDY: This study unveils the antifungal potential of THP, a known respiratory drug that can be further utilized for a wider range of applications such as combating fungal infections. The effect of THP with the known antifungal drugs can be exploited in the combinatorial drug approach for treating candidiasis.

PMID: 32320111 [PubMed - as supplied by publisher]

Repurposing Auranofin, an Anti-Rheumatic Gold Compound, to Treat Acne Vulgaris by Targeting the NLRP3 Inflammasome.

Biomol Ther (Seoul). 2020 Apr 22;:

Authors: Yang G, Lee SJ, Kang HC, Cho YY, Lee HS, Zouboulis CC, Han SH, Ma KH, Jang JK, Lee JY

Abstract
Activation of the NLRP3 inflammasome is critical for host defense as well as the progression of inflammatory diseases through the production of the proinflammatory cytokine IL-1β, which is cleaved by active caspase-1. It has been reported that overactivation of the NLRP3 inflammasome contributes to the development and pathology of acne vulgaris. Therefore, inhibiting activation of the NLRP3 inflammasome may provide a new therapeutic strategy for acne vulgaris. In this study, we investigated whether auranofin, an anti-rheumatoid arthritis agent, inhibited NLRP3 inflammasome activation, thereby effectively treating acne vulgaris. Auranofin suppressed NLRP3 inflammasome activation induced by Propionibacterium acnes, reducing the production of IL-1β in primary mouse macrophages and human sebocytes. In a P. acnes-induced acne mouse model, injection of P. acnes into the ears of mice induced acne symptoms such as redness, swelling, and neutrophil infiltration. Topical application of auranofin (0.5 or 1%) to mouse ears significantly reduced the inflammatory symptoms of acne vulgaris induced by P. acnes injection. Topical application of auranofin led to the downregulation of the NLRP3 inflammasome activated by P. acnes in mouse ear skin. These results show that auranofin inhibits the NLRP3 inflammasome, the activation of which is associated with acne symptoms. The results further suggest that topical application of auranofin could be a new therapeutic strategy for treating acne vulgaris by targeting the NLRP3 inflammasome.

PMID: 32319265 [PubMed - as supplied by publisher]

Perspectives for repurposing drugs for the coronavirus disease 2019.

Indian J Med Res. 2020 Apr 10;:

Authors: Cherian SS, Agrawa M, Basu A, Abraham P, Gangakhedkar RR, Bhargava B

Abstract
The newly emerged 2019 novel coronavirus (CoV), named as severe acute respiratory syndrome CoV-2 (SARS-CoV-2), like SARS-CoV (now, SARS-CoV-1) and Middle East respiratory syndrome CoV (MERS-CoV), has been associated with high infection rates with over 36,405 deaths. In the absence of approved marketed drugs against coronaviruses, the treatment and management of this novel CoV disease (COVID-19) worldwide is a challenge. Drug repurposing that has emerged as an effective drug discovery approach from earlier approved drugs could reduce the time and cost compared to de novo drug discovery. Direct virus-targeted antiviral agents target specific nucleic acid or proteins of the virus while host-based antivirals target either the host innate immune responses or the cellular machineries that are crucial for viral infection. Both the approaches necessarily interfere with viral pathogenesis. Here we summarize the present status of both virus-based and host-based drug repurposing perspectives for coronaviruses in general and the SARS-CoV-2 in particular.

PMID: 32317408 [PubMed - as supplied by publisher]

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

Turk J Med Sci. 2020 04 21;50(SI-1):620-632

Authors: Tufan A, Avanoğlu Güler A, Matucci-Cerinic M

Abstract
In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines “cytokine storm” leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.

PMID: 32299202 [PubMed - indexed for MEDLINE]

Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) Through Computational Drug Repurposing Study.

J Chem Inf Model. 2020 Apr 21;:

Authors: Wang J

Abstract
The recent outbreak of novel coronavirus disease -19 (COVID-19) calls for and welcomes possible treatment strategies using drugs on the market. It is very efficient to apply computer-aided drug design techniques to quickly identify promising drug repurposing candidates, especially after the detailed 3D-structures of key virous proteins are resolved. The virus causing COVID-19 is SARS-Cov-2. Taking the advantage of a recently released crystal structure of SARS-Cov-2 main protease in complex with a covalently-bonded inhibitor, N3,1 I conducted virtual docking screening of approved drugs and drug candidates in clinical trials. For the top docking hits, I then performed molecular dynamics simulations followed by binding free energy calculations using an endpoint method called MM-PBSA-WSAS (Molecular Mechanics-Poisson Boltzmann Surface Area-Weighted Solvent-Accessible Surface Area).2-4 Several promising known drugs stand out as potential inhibitors of SARS-Cov-2 main protease, including Carfilzomib, Eravacycline, Valrubicin, Lopinavir and Elbasvir. Carfilzomib, an approved anti-cancer drug acting as a proteasome inhibitor, has the best MM-PBSA-WSAS binding free energy, -13.8 kcal/mol. The second-best repurposing drug candidate, eravacycline, is synthetic halogenated tetracycline class antibiotic. Streptomycin, another antibiotic and a charged molecule, also demonstrates some inhibitory effect, even though the predicted binding free energy of the charged form (-3.8 kcal/mol) is not nearly as low as that of the neutral form (-7.9 kcal/mol). One bioactive, PubChem 23727975, has a binding free energy of -12.9 kcal/mol. Detailed receptor-ligand interactions were analyzed and hot spots for the receptor-ligand binding were identified. I found that one hotspot residue HIS41, is a conserved residue across many viruses including SARS-Cov, SARS-Cov-2, MERS-Cov, and HCV. The findings of this study can facilitate rational drug design targeting the SARS-Cov-2 main protease.

PMID: 32315171 [PubMed - as supplied by publisher]

Repurposing Doxepin to Ameliorate Steatosis and Hyperglycemia by Activating FAM3A Signaling Pathway.

Diabetes. 2020 Apr 20;:

Authors: Chen Z, Liu X, Luo Y, Wang J, Meng Y, Sun L, Chang Y, Cui Q, Yang J

Abstract
Mitochondrial protein FAM3A suppresses hepatic gluconeogenesis and lipogenesis. This study aimed to screen drug(s) that activates FAM3A expression and evaluate its effect(s) on hyperglycemia and steatosis. Drug-repurposing methodology predicted that antidepressive drug doxepin was among the drugs that potentially activated FAM3A expression. Doxepin was further validated to stimulate the translocation of transcription factor HNF4α from the cytoplasm into the nucleus, where it promoted FAM3A transcription to enhance ATP synthesis, suppress gluconeogenesis, and reduce lipid deposition in hepatocytes. HNF4α antagonism or FAM3A deficiency blunted doxepin-induced suppression on gluconeogenesis and lipid deposition in hepatocytes. Doxepin administration attenuated hyperglycemia, steatosis, and obesity in obese diabetic mice with upregulated FAM3A expression in liver and brown adipose tissues (BAT). Notably, doxepin failed to correct dysregulated glucose and lipid metabolism in FAM3A-deficient mice fed on high-fat diet. Doxepin's effects on ATP production, Akt activation, gluconeogenesis, and lipogenesis repression were also blunted in FAM3A-deficient mouse livers. In conclusion, FAM3A is a therapeutic target for diabetes and steatosis. Antidepressive drug doxepin activates FAM3A signaling pathways in liver and BAT to improve hyperglycemia and steatosis of obese diabetic mice. Doxepin might be preferentially recommended as an antidepressive drug in potential treatment of patients with diabetes complicated with depression.

PMID: 32312868 [PubMed - as supplied by publisher]

Mebendazole elicits potent antimyeloma activity by inhibiting the USP5/c-Maf axis.

Acta Pharmacol Sin. 2019 Dec;40(12):1568-1577

Authors: Chen XH, Xu YJ, Wang XG, Lin P, Cao BY, Zeng YY, Wang Q, Zhang ZB, Mao XL, Zhang T

Abstract
c-Maf is a critical oncogenic transcription factor that contributes to myelomagenesis. Our previous studies demonstrated that the deubiquitinase USP5 stabilizes c-Maf and promotes myeloma cell proliferation and survival; therefore, the USP5/c-Maf axis could be a potential target for myeloma therapy. As a concept of principle, the present study established a USP5/c-Maf-based luciferase system that was used to screen an FDA-approved drug library. It was found that mebendazole, a typical anthelmintic drug, preferentially induced apoptosis in c-Maf-expressing myeloma cells. Moreover, oral administration of mebendazole delayed the growth of human myeloma xenografts in nude mice but did not show overt toxicity. Further studies showed that the selective antimyeloma activity of mebendazole was associated with the inhibition of the USP5/c-Maf axis. Mebendazole downregulated USP5 expression and disrupted the interaction between USP5 and c-Maf, thus leading to increased levels of c-Maf ubiquitination and subsequent c-Maf degradation. Mebendazole inhibited c-Maf transcriptional activity, as confirmed by both luciferase assays and expression measurements of c-Maf downstream genes. In summary, this study identified mebendazole as a USP5/c-Maf inhibitor that could be developed as a novel antimyeloma agent.

PMID: 31197245 [PubMed - indexed for MEDLINE]