In Search of Outliers. Mining for Protein Kinase Inhibitors Based on Their Anti-Proliferative NCI-60 Cell Lines Profile.

Molecules. 2020 Apr 11;25(8):

Authors: Ion GND, Nitulescu GM

Abstract
Protein kinases play a pivotal role in signal transduction, protein synthesis, cell growth and proliferation. Their deregulation represents the basis of pathogenesis for numerous diseases such as cancer and pathologies with cardiovascular, nervous and inflammatory components. Protein kinases are an important target in the pharmaceutical industry, with 48 protein kinase inhibitors (PKI) already approved on the market as treatments for different afflictions including several types of cancer. The present work focuses on facilitating the identification of new PKIs with antitumoral potential through the use of data-mining and basic statistics. The National Cancer Institute (NCI) granted access to the results of numerous previously tested compounds on 60 tumoral cell lines (NCI-60 panel). Our approach involved analyzing the NCI database to identify compounds that presented similar growth inhibition (GI) profiles to that of existing PKIs, but different from approved oncologic drugs with other mechanisms of action, using descriptive statistics and statistical outliers. Starting from 34,000 compounds present in the database, we filtered 400 which displayed selective inhibition on certain cancer cell lines similar to that of several already-approved PKIs.

PMID: 32290461 [PubMed - in process]

A Review of SARS-CoV-2 and the Ongoing Clinical Trials.

Int J Mol Sci. 2020 Apr 10;21(7):

Authors: Tu YF, Chien CS, Yarmishyn AA, Lin YY, Luo YH, Lin YT, Lai WY, Yang DM, Chou SJ, Yang YP, Wang ML, Chiou SH

Abstract
The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) in Wuhan, China, which rapidly grew into a global pandemic, marked the third introduction of a virulent coronavirus into the human society, affecting not only the healthcare system, but also the global economy. Although our understanding of coronaviruses has undergone a huge leap after two precedents, the effective approaches to treatment and epidemiological control are still lacking. In this article, we present a succinct overview of the epidemiology, clinical features, and molecular characteristics of SARS-CoV-2. We summarize the current epidemiological and clinical data from the initial Wuhan studies, and emphasize several features of SARS-CoV-2, which differentiate it from SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), such as high variability of disease presentation. We systematize the current clinical trials that have been rapidly initiated after the outbreak of COVID-19 pandemic. Whereas the trials on SARS-CoV-2 genome-based specific vaccines and therapeutic antibodies are currently being tested, this solution is more long-term, as they require thorough testing of their safety. On the other hand, the repurposing of the existing therapeutic agents previously designed for other virus infections and pathologies happens to be the only practical approach as a rapid response measure to the emergent pandemic, as most of these agents have already been tested for their safety. These agents can be divided into two broad categories, those that can directly target the virus replication cycle, and those based on immunotherapy approaches either aimed to boost innate antiviral immune responses or alleviate damage induced by dysregulated inflammatory responses. The initial clinical studies revealed the promising therapeutic potential of several of such drugs, including favipiravir, a broad-spectrum antiviral drug that interferes with the viral replication, and hydroxychloroquine, the repurposed antimalarial drug that interferes with the virus endosomal entry pathway. We speculate that the current pandemic emergency will be a trigger for more systematic drug repurposing design approaches based on big data analysis.

PMID: 32290293 [PubMed - in process]

"What Were You Before the War?" Repurposing Psychiatry During the COVID-19 Pandemic.

J Clin Psychiatry. 2020 04 07;81(3):

Authors: Nicol GE, Karp JF, Reiersen AM, Zorumski CF, Lenze EJ

PMID: 32271506 [PubMed - indexed for MEDLINE]

Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling approach for effective drug repurposing.

Clin Pharmacol Ther. 2020 Apr 14;:

Authors: Garcia-Cremades M, Solans BP, Hughes E, Ernest JP, Wallender E, Aweeka F, Luetkemeyer A, Savic RM

Abstract
Hydroxychloroquine (HCQ) is a promising candidate for Coronavirus Disease of 2019 (COVID-19) treatment. The optimal dosing of HCQ is unknown. Our goal was to integrate historic and emerging pharmacological and toxicity data to understand safe and efficacious HCQ dosing strategies for COVID-19 treatment. The data sources included were 1) longitudinal clinical, pharmacokinetic, and virologic data from patients with severe acute respiratory syndrome-2 (SARS-CoV-2) infection who received HCQ with or without azithromycin (n=116), 2) in vitro viral replication data and SARS-CoV-2 viral load inhibition by HCQ, 3) a population pharmacokinetic model of HCQ and 4) a model relating chloroquine pharmacokinetics to QTc prolongation. A mechanistic PK/virologic/QTc model for HCQ was developed and externally validated to predict SARS-CoV-2 rate of viral decline and QTc prolongation. SARS-CoV-2 viral decline was associated with HCQ pharmacokinetics (p<0.001). The extrapolated patient EC50 was 4.7 µM, comparable to the reported in vitro EC50 's. HCQ doses > 400 mg BID for ≥5 days were predicted to rapidly decrease viral loads, reduce the proportion of patients with detectable SARS-CoV-2 infection, and shorten treatment courses, compared to lower dose (≤400 mg daily) regimens. However, HCQ doses >600 mg BID were also predicted to prolong QTc intervals. This prolongation may have clinical implications warranting further safety assessment. Due to COVID-19's variable natural history, lower dose HCQ regimens may be indistinguishable from controls. Evaluation of higher HCQ doses is needed to ensure adequate safety and efficacy.

PMID: 32285930 [PubMed - as supplied by publisher]

Strategies for Zika drug discovery.

Curr Opin Virol. 2019 04;35:19-26

Authors: Zou J, Shi PY

Abstract
Zika virus (ZIKV) can cause devastating congenital syndrome in fetuses from pregnant women and autoimmune disorder Guillain-Barré syndrome in adults. No clinically approved vaccine or drug is currently available for ZIKV. This unmet medical need has motivated a global effort to develop countermeasures. Several promising ZIKV vaccine candidates have already entered clinical trials. In contrast, antiviral development of ZIKV is lagging behind. Here, we review the overall strategies for ZIKV drug discovery, including (i) repurposing of clinically approved drugs, (ii) viral replication-based phenotypic screening for inhibitors, and (iii) targeted drug discovery of viral proteins. Along with vaccines, the development of antiviral treatment will provide a complementary means to control ZIKV infections.

PMID: 30852345 [PubMed - indexed for MEDLINE]

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Old drug repurposing for neglected disease: Pyronaridine as a promising candidate for the treatment of Echinococcus granulosus infections.

EBioMedicine. 2020 Apr 09;54:102711

Authors: Li J, Wang W, Yao J, Wang T, Li S, Qi W, Han S, Ren Y, Dang Z, Han X, Guo G, Guo B, Wang L, Duan L, Zhang W

Abstract
BACKGROUND: Cystic echinococcosis (CE), a condition caused by the larval stage of the dog tapeworm Echinococcus granulosus sensu stricto, is a globally distributed zoonotic disease. Current treatment options for CE are limited, and an effective and safe anti-echinococcal drug is urgently required.
METHODS: Drug repurposing strategy was employed to identify new therapeutic agents against echinococcal cysts. An in vitro protoscolicidal assay along with in vivo murine models was applied in the drug screening. A microinjection procedure was employed to mimic the clinical PAIR (puncture, aspiration, injection and reaspiration) technique to evaluate the potential application of the candidate drug in clinical practice.
FINDINGS: We repurposed pyronaridine, an approved antimalarial drug, for the treatment of CE. Following a three-dose intraperitoneal regimen (57 mg/kg, q.d. for 3 days), pyronaridine caused 100% cyst mortality. Oral administration of pyronaridine at 57 mg/kg, q.d. for 30 days significantly reduced the parasitic burden in the pre-infected mice compared with albendazole group (p < 0.001). Using a microinjection of drug into cysts, pyronaridine (200 μM) showed highly effective in term of inhibition of cyst growth (p < 0.05, compared with saline group). Pharmacokinetic analysis revealed that pyronaridine was highly distributed in the liver and lungs, the most affected organs of CE. Function analysis showed that pyronaridine inhibited the activity of topoisomerase I (IC50 = 209.7 ± 1.1 μM). In addition, classical apoptotic hallmarks, including DNA fragmentation and caspase activation, were triggered.
INTERPRETATION: Given its approved clinical safety, the repurposing of pyronaridine offers a rapidly translational option for treating CE including PAIR. FUND: National Natural Science Foundation of China and International Cooperation Project of the Qinghai Science and Technology Department.

PMID: 32279056 [PubMed - as supplied by publisher]

Drug repositioning an alternative for the treatment of coronavirus COVID-19.

Int J Antimicrob Agents. 2020 Apr 09;:105969

Authors: Serafin MB, Bottega A, Foletto VS, da Rosa TF, Hörner A, Hörner R

Abstract
Given the extreme importance of the current pandemic caused by COVID-19, and due to the fact that scientists agree that there is no identified pharmacological treatment where possible therapeutic alternatives are raised through drug repositioning. We present a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-Cov, with potential use in the treatment of COVID-19 disease.

PMID: 32278811 [PubMed - as supplied by publisher]

Hutchinson-Gilford Progeria Syndrome: Rejuvenating old drugs to fight accelerated ageing.

Methods. 2020 Apr 09;:

Authors: Guilbert SM, Cardoso D, Lévy N, Muchir A, Nissan X

Abstract
What if the next generation of successful treatments was hidden in the current pharmacopoeia? Identifying new indications for existing drugs, also called the drug repurposing or drug rediscovery process, is a highly efficient and low-cost strategy. First reported almost a century ago, drug repurposing has emerged as a valuable therapeutic option for diseases that do not have specific treatments and rare diseases, in particular. This review focuses on Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder that induces accelerated and precocious aging, for which drug repurposing has led to the discovery of several potential treatments over the past decade.

PMID: 32278808 [PubMed - as supplied by publisher]

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach.

Life Sci. 2020 Apr 09;:117652

Authors: Shah B, Modi P, Sagar SR

Abstract
AIMS: The severe acute respiratory syndrome coronavirus 2, better known as COVID-19 has become the current health concern to the entire world. Initially appeared in Wuhan, China around December 2019, it had spread to almost 187 countries due to its high contagious nature. Precautionary measures remain the sole obliging tactic to cease the person to person transmissions till any effective method of treatment or vaccine is developed. Amidst the pandemic, research and development of new molecule is labour-intensive and tedious process. Drug repurposing is the concept of identifying therapeutically potent molecule from the library of pre-existing molecules.
MATERIALS AND METHODS: In the present study, 61 molecules that are already being used in clinics or under clinical scrutiny as antiviral agents are surveyed via docking study. Docking study was performed using Maestro interface (Schrödinger Suite, LLC, NY).
KEY FINDINGS: Out of these 61 molecules, 37 molecules were found to interact with >2 protein structures of COVID-19. The docking results indicate that amongst the reported molecules, HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors showed promising features of binding to COVID-19 enzyme. Along with these, Methisazone an inhibitor of protein synthesis, CGP42112A an angiotensin AT2 receptor agonist and ABT450 an inhibitor of the non-structural protein 3-4A might become convenient treatment option as well against COVID-19.
SIGNIFICANCE: The drug repurposing approach provide an insight about the therapeutics that might be helpful in treating corona virus disease.

PMID: 32278693 [PubMed - as supplied by publisher]

Mebendazole is a potent inhibitor to chemoresistant T cell acute lymphoblastic leukemia cells.

Toxicol Appl Pharmacol. 2020 Apr 08;:115001

Authors: Wang X, Lou K, Song X, Ma H, Zhou X, Xu H, Wang W

Abstract
Mebendazole (MBZ) is a tubulin-suppressive antihelmintic agent with low toxicity, which has been repurposed to treat different types of tumors. Chemoresistance is quite common in refractory or relapsed T cell acute lymphoblastic leukemia (T-ALL), which leads to dismal chances of recovery. In this study, MBZ was found to suppress the proliferation and reduce the viability of T-ALL cell line, CCRF-CEM, and its chemoresistant derivative, CEM/C1, at nanomolar concentrations. The inhibitive effects were found to be dose-dependent and not to be affected by the chemoresistance of CEM/C1 cells. Cell cycle arrest, caspase 3/7 activation and tubulin disruption were found in the MBZ-treated T-ALL cells. Notch1 signaling, which is often aberrantly activated in T-ALL cells, was showed to be suppressed by MBZ treatments. MBZ administration in murine T-ALL models also suppressed the growth of CEM/C1 cells, indicating that MBZ may be developed as a therapeutic agent for chemoresistant T-ALLs. The mRNA levels of the Notch1 and Hes1 were also confirmed to be suppressed by MBZ in vivo, which was consistent with the in vitro observations. This study demonstrated, for the first time, that MBZ could inhibit chemoresistant T-ALL cells both in vitro and in vivo, and the Notch1 signaling pathway was suppressed by MBZ treatment.

PMID: 32277947 [PubMed - as supplied by publisher]

Artificial intelligence and machine learning to fight COVID-19.

Physiol Genomics. 2020 04 01;52(4):200-202

Authors: Alimadadi A, Aryal S, Manandhar I, Munroe PB, Joe B, Cheng X

PMID: 32216577 [PubMed - indexed for MEDLINE]

Potentiation of P2RX7 as a host-directed strategy for control of mycobacterial infection.

Elife. 2019 01 29;8:

Authors: Matty MA, Knudsen DR, Walton EM, Beerman RW, Cronan MR, Pyle CJ, Hernandez RE, Tobin DM

Abstract
Mycobacterium tuberculosis is the leading worldwide cause of death due to a single infectious agent. Existing anti-tuberculous therapies require long treatments and are complicated by multi-drug-resistant strains. Host-directed therapies have been proposed as an orthogonal approach, but few have moved into clinical trials. Here, we use the zebrafish-Mycobacterium marinum infection model as a whole-animal screening platform to identify FDA-approved, host-directed compounds. We identify multiple compounds that modulate host immunity to limit mycobacterial disease, including the inexpensive, safe, and widely used drug clemastine. We find that clemastine alters macrophage calcium transients through potentiation of the purinergic receptor P2RX7. Host-directed drug activity in zebrafish larvae depends on both P2RX7 and inflammasome signaling. Thus, targeted activation of a P2RX7 axis provides a novel strategy for enhanced control of mycobacterial infections. Using a novel explant model, we find that clemastine is also effective within the complex granulomas that are the hallmark of mycobacterial infection.

PMID: 30693866 [PubMed - indexed for MEDLINE]

An overview of drug discovery and development.

Future Med Chem. 2020 Apr 09;:

Authors: Berdigaliyev N, Aljofan M

Abstract
A new medicine will take an average of 10-15 years and more than US$2 billion before it can reach the pharmacy shelf. Traditionally, drug discovery relied on natural products as the main source of new drug entities, but was later shifted toward high-throughput synthesis and combinatorial chemistry-based development. New technologies such as ultra-high-throughput drug screening and artificial intelligence are being heavily employed to reduce the cost and the time of early drug discovery, but they remain relatively unchanged. However, are there other potentially faster and cheaper means of drug discovery? Is drug repurposing a viable alternative? In this review, we discuss the different means of drug discovery including their advantages and disadvantages.

PMID: 32270704 [PubMed - as supplied by publisher]

Inhibiting exosomal MIC-A and MIC-B shedding of cancer cells to overcome immune escape: new insight of approved drugs.

Daru. 2019 Dec;27(2):879-884

Authors: Moloudizargari M, Asghari MH, Mortaz E

Abstract
Our knowledge of the role of innate immunity in protecting against cancers has expanded greatly in recent years. An early focus was on the adoptive transfer of natural killer (NK) cells and, although this approach has demonstrated promising results in many patients, a few limitations including immune escape of tumors from cytotoxic killing by NK cells have caused treatment failures. Downregulation of the expression of activating ligands on the surface of cancer cells and prevention of the activity of soluble factors are among the mechanisms employed by cancer cells to overcome NK-mediated immunity. It has become evident that a class of small membranous structures of endosomal origin known as exosomes play a key role in regulating the local tumor microenvironment. Here we hypothesize that exosome secretion by cancer cells, which is greater than that of normal cells, is an important escape mechanism employed by cancer cells. Interruption of exosome release by various inhibitory agents in combination with the adoptive transfer of NK cells may overcome, at least in part, the treatment failures that occur with adoptive NK cell transfer. In this regard, repositioning of approved drugs with previously shown effects on exosome release may be a good strategy to bypass the safety issues of newly identified agents and will also dramatically reduce the huge costs of drug approval process.

PMID: 31435903 [PubMed - indexed for MEDLINE]

Antimalarial drugs and their metabolites are potent Zika virus inhibitors.

J Med Virol. 2019 07;91(7):1182-1190

Authors: Han Y, Pham HT, Xu H, Quan Y, Mesplède T

Abstract
Studies aimed at repurposing existing drugs revealed that some antimalarial compounds possess anti-Zika virus (anti-ZIKV) activity. Here, we further tested 14 additional antimalarial drugs and their metabolites or analogs for anti-ZIKV activity using a phenotypic screening approach. We identified four compounds with varying anti-ZIKV activity, including a metabolite of amodiaquine termed desethylamodiaquine (DAQ) and N-desethylchloroquine (DECQ), a metabolite of chloroquine, which both exhibited low micromolar effective concentrations against three different ZIKV strains. Two other compounds termed dihydroartemisinin (DHA) and quinidine (QD) exhibited only partial inhibition of ZIKV replication. Characterization of the inhibitory mechanisms of DAQ and DECQ showed that both drugs target the entry step as well as postentry events of the viral replication cycle. These hits represent attractive starting points for future optimization of new anti-ZIKV drug candidates derived from antimalarial drugs and their analogs.

PMID: 30801742 [PubMed - indexed for MEDLINE]

Computational prediction of drug-target interactions using chemogenomic approaches: an empirical survey.

Brief Bioinform. 2019 07 19;20(4):1337-1357

Authors: Ezzat A, Wu M, Li XL, Kwoh CK

Abstract
Computational prediction of drug-target interactions (DTIs) has become an essential task in the drug discovery process. It narrows down the search space for interactions by suggesting potential interaction candidates for validation via wet-lab experiments that are well known to be expensive and time-consuming. In this article, we aim to provide a comprehensive overview and empirical evaluation on the computational DTI prediction techniques, to act as a guide and reference for our fellow researchers. Specifically, we first describe the data used in such computational DTI prediction efforts. We then categorize and elaborate the state-of-the-art methods for predicting DTIs. Next, an empirical comparison is performed to demonstrate the prediction performance of some representative methods under different scenarios. We also present interesting findings from our evaluation study, discussing the advantages and disadvantages of each method. Finally, we highlight potential avenues for further enhancement of DTI prediction performance as well as related research directions.

PMID: 29377981 [PubMed - indexed for MEDLINE]

Targeting SARS-CoV-2: A Systematic Drug Repurposing Approach to Identify Promising Inhibitors Against 3C-like Proteinase and 2'-O-RiboseMethyltransferase.

J Biomol Struct Dyn. 2020 Apr 08;:1-40

Authors: Khan RJ, Jha RK, Amera G, Jain M, Singh E, Pathak A, Singh RP, Muthukumaran J, Singh AK

Abstract
The recent pandemic associated with SARS-CoV-2, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify promising inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG= -9.8 kcal/mol) &Raltegravir (ΔG= -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG= -9.4 kcal/mol) and Bictegravir (ΔG= -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against SARS-CoV-2.

PMID: 32266873 [PubMed - as supplied by publisher]

TRPC3-based protein signaling complex as a therapeutic target of myocardial atrophy.

Curr Mol Pharmacol. 2020 Apr 06;:

Authors: Nishiyama K, Tanaka T, Nishimura A, Nishida M

Abstract
BACKGROUND: Transient receptor potential (TRP) channels, especially canonical TRP channel subfamily members 3 (TRPC3) and 6 (TRPC6), have attracted attention as a putative therapeutic target of heart | 1 failure. Moreover, TRPC3 and TRPC6 channels are physiologically important for maintaining cellular homeostasis. How TRPC3/C6 channels alter intracellular signaling from adaptation to maladaptation has been discussed for many years. We recently showed that formation of a protein signal complex between TRPC3 and NADPH oxidase (Nox) 2 caused by environmental stresses (e.g., hypoxia, nutritional deficiency, and anticancer drug treatment) promotes Nox2-dependent reactive oxygen species production and cardiac stiffness, including myocardial atrophy and interstitial fibrosis, in rodents. In fact, pharmacological prevention of the TRPC3-Nox2 protein complex can maintain cardiac flexibility in mice after anti-cancer drug treatment.
CONCLUSION: In this mini-review, we discuss the relationship between TRPC3/C6 channels and cardiovascular disease, and propose a new therapeutic strategy by focusing on pathology-specific protein- protein interactions.

PMID: 32264816 [PubMed - as supplied by publisher]

An in situ high-throughput screen identifies inhibitors of intracellular Burkholderia pseudomallei with therapeutic efficacy.

Proc Natl Acad Sci U S A. 2019 09 10;116(37):18597-18606

Authors: Bulterys PL, Toesca IJ, Norris MH, Maloy JP, Fitz-Gibbon ST, France B, Toffig B, Morselli M, Somprasong N, Pellegrini M, Schweizer HP, Tuanyok A, Damoiseaux R, French CT, Miller JF

Abstract
Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Tier-1 Select Agents that cause melioidosis and glanders, respectively. These are highly lethal human infections with limited therapeutic options. Intercellular spread is a hallmark of Burkholderia pathogenesis, and its prominent ties to virulence make it an attractive therapeutic target. We developed a high-throughput cell-based phenotypic assay and screened ∼220,000 small molecules for their ability to disrupt intercellular spread by Burkholderia thailandensis, a closely related BSL-2 surrogate. We identified 268 hits, and cross-species validation found 32 hits that also disrupt intercellular spread by Bp and/or Bm Among these were a fluoroquinolone analog, which we named burkfloxacin (BFX), which potently inhibits growth of intracellular Burkholderia, and flucytosine (5-FC), an FDA-approved antifungal drug. We found that 5-FC blocks the intracellular life cycle at the point of type VI secretion system 5 (T6SS-5)-mediated cell-cell spread. Bacterial conversion of 5-FC to 5-fluorouracil and subsequently to fluorouridine monophosphate is required for potent and selective activity against intracellular Burkholderia In a murine model of fulminant respiratory melioidosis, treatment with BFX or 5-FC was significantly more effective than ceftazidime, the current antibiotic of choice, for improving survival and decreasing bacterial counts in major organs. Our results demonstrate the utility of cell-based phenotypic screening for Select Agent drug discovery and warrant the advancement of BFX and 5-FC as candidate therapeutics for melioidosis in humans.

PMID: 31439817 [PubMed - indexed for MEDLINE]