Tea tree oil, a vibrant source of neuroprotection via neuroinflammation inhibition: a critical insight into repurposing Melaleuca alternifolia by unfolding its characteristics / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Over the past few decades, complementary and alternative treatments have become increasingly popular worldwide. The purported therapeutic characteristics of natural products have come under increased scrutiny both in vitro and in vivo as part of efforts to legitimize their usage. One such product is tea tree oil (TTO), a volatile essential oil primarily obtained from the native Australian plant, Melaleuca alternifolia, which has diverse traditional and industrial applications such as topical preparations for the treatment of skin infections. Its anti-inflammatory-linked immunomodulatory actions have also been reported. This systematic review focuses on the anti-inflammatory effects of TTO and its main components that have shown strong immunomodulatory potential. An extensive literature search was performed electronically for data curation on worldwide accepted scientific databases, such as Web of Science, Google Scholar, PubMed, ScienceDirect, Scopus, and esteemed publishers such as Elsevier, Springer, Frontiers, and Taylor & Francis. Considering that the majority of pharmacological studies were conducted on crude oils only, the extracted data were critically analyzed to gain further insight into the prospects of TTO being used as a neuroprotective agent by drug formulation or dietary supplement. In addition, the active constituents contributing to the activity of TTO have not been well justified, and the core mechanisms need to be unveiled especially for anti-inflammatory and immunomodulatory effects leading to neuroprotection. Therefore, this review attempts to correlate the anti-inflammatory and immunomodulatory activity of TTO with its neuroprotective mechanisms.

Prospecção de novos candidatos a fármacos antituberculose: uma abordagem in vitro / Prospecting new candidates for antituberculosis drugs: an in vitro approach

A tuberculose (TB) é uma doença infecciosa causada pelo Mycobacterium tuberculosis que apresenta alta morbidade e mortalidade. Atualmente, a tuberculose afeta 9,9 milhões de pessoas em todo o mundo e é responsável por cerca de 1,3 milhões de mortes, sendo um sério problema de Saúde Pública global. O tratamento da TB é composto por uma associação de fármacos e dura seis meses. A frequência de doentes infectados com isolados resistentes aos fármacos de primeira linha, principalmente os isolados multirresistentes, é uma ameaça mundial que caracteriza um importante problema de saúde pública no controle da TB em vários países. Existem poucos medicamentos para o tratamento da TB muti-resistente e com base nesta problemática o presente estudo visou a avaliação do potencial farmacológico in vitro de fármacos aprovados, utilizando a abordagem de reposicionamento de fármacos. A partir de uma triagem in vitro de 89 fármacos, foram selecionados os que apresentaram atividade antituberculose para a avaliação da concentração inibitória mínima, os fármacos foram avaliados em exposição a 23 isolados do complexo Mycobacterium tuberculosis e a cepa ATCC H37 RV 27294 in vitro utilizando o ensaio de resazurina. Além disso, foram realizados ensaios de citotoxicidade contra células de mamíferos NCTC L929 em cultura, determinando-se os Índices de Seletividade in vitro. Dentre os 89 fármacos testados, quatro (amiodarona, flunarizina, ivermectina e pentamidina) apresentaram atividade antituberculose a 10 µM. A Concentração Inibitória Mínima (CIM) 90% da amiodarona resultou em 5-10 µM, flunarizina 10 µM, ivermectina 0,15 ­ 10 µM e pentamidina 1,25-10 µM. Os índices de seletividade observados para a amiodarona foram de 4,21 ­ 8,43, flunarizina >20, ivermectina 1,17 ­ 78,47 e pentamidina 14,40 ­ 115,2. Com base na atividade e citotoxicidade da amiodarona, foi realizado um ensaio fluorimétrico utilizando Sytox Green para avaliar a permeabilidade de membrana plasmática do complexo M. tuberculosis na presença deste fármaco. Foi observado que a amiodarona não alterou a permeabilidade da membrana plasmática do Complexo M. tuberculosis, tendo seu mecanismo de ação letal por outra via.

Innovative pharmaceutical strategies for niclosamide repositioning / Estratégias farmacêuticas inovadoras para o reposicionamento da niclosamida

The antiparasitic niclosamide has shown promising anticancer activity in preclinical studies against several types of cancer, such as colorectal and prostate. Thus, the objective of this work was to develop innovative formulations for the repositioning of niclosamide as an anticancer agent. In chapter I, a critical review of the literature on the physicochemical properties of the drug was carried out, in addition the results of clinical studies against colorectal and prostate cancer. Besides, a review was carried out on studies that developed formulations containing this drug, as well as hypotheses to improve the biopharmaceutical performance of this molecule. In chapter II, the development of solid amorphous dispersion containing niclosamide was carried out. Drug/polymer solutions were acoustic levitated and characterized by synchrotron X-ray light. This set allowed fast, high quality measurements, as well as the identification of niclosamide recrystallization. Plasdone® and Soluplus® demonstrated better properties to form amorphous dispersions, with the latter showing superior solubility enhancement. The study showed that the developed formulation increased the apparent saturation solubility of niclosamide in water by two times. In chapter III the objective was the development, physicochemical characterization and in vitro anticancer activity of a niclosamide nanoemulsion, having HCT-116 cells as a cellular model. Preliminary results indicated Capmul® MCM C8 as the best liquid lipid for the system, but the first nanoemulsions containing this lipid were not stable to justify its usage. On the other hand, Miglyol® 812 indicated to be a suitable liquid lipid for the system. The niclosamide nanoemulsion (~200 nm) with Miglyol® 812 and poloxamer 188 was stable for 56 days, with a monomodal particle size distribution. Cell viability assay against HCT-116 cells demonstrated that niclosamide cytotoxicity is time and concentration dependent. Results herein obtained encourage further research to understand and optimize niclosamide performance as an anticancer drug substance

O antiparasitário niclosamida tem apresentado promissora atividade anticâncer em estudos pré- clínicos contra diversos tipos de câncer, como coloretal e próstata. Assim, o objetivo deste trabalho foi desenvolver formulações inovadoras para o reposicionamento da niclosamida como agente anticâncer. No capítulo I foi realizada revisão crítica da literatura sobre as propriedades físico-químicas do fármaco, além de resultados de estudos clínicos da niclosamida contra câncer de coloretal e de próstata. Além disso, foi feita revisão sobre estudos que desenvolveram formulações contendo esse fármaco, bem como hipóteses para melhorar o desempenho biofarmacêutico dessa molécula. No capítulo II foi realizado o desenvolvimento de dispersão solida amorfa contendo niclosamida. Soluções de fármaco/polímero foram levitadas em levitador acústico e caracterizadas por raios-X de luz síncrotron. Este conjunto permitiu medições rápidas e de alta qualidade, bem como identificação de recristalização da niclosamida. Plasdone® e Soluplus® demonstraram melhores propriedades para formar as dispersões amorfas, com o último apresentando aumento de solubilidade superior. O estudo mostrou que a formulação desenvolvida aumentou em duas vezes a solubilidade aparente de saturação da niclosamida em água. No capítulo III o objetivo foi o desenvolvimento, a caracterização físicoquímica e atividade anticâncer in vitro de uma nanoemulsão de niclosamida, tendo células HCT-116 como modelo celular. Resultados preliminares indicaram o Capmul® MCM C8 como o melhor lipídio líquido para o sistema, mas as primeiras nanoemulsões contendo este lipídio não foram estáveis para justificar seu uso. Por outro lado, Miglyol® 812 indicou ser um lipídio líquido adequado para o sistema. A nanoemulsão de niclosamida (~200 nm) com Miglyol® 812 e poloxâmero 188 foi estável por 56 dias, com distribuição monomodal do tamanho de partícula. O ensaio de viabilidade celular contra células HCT-116 demonstrou que a citoxicidade da niclosamida é dependente do tempo e da concentração. Os resultados aqui obtidos encorajam mais pesquisas para entender e otimizar o desempenho da niclosamida como uma substância anticancerígena

Discovery and repurposing of artemisinin / 医学前沿

Malaria is an ancient infectious disease that threatens millions of lives globally even today. The discovery of artemisinin, inspired by traditional Chinese medicine (TCM), has brought in a paradigm shift and been recognized as the "best hope for the treatment of malaria" by World Health Organization. With its high potency and low toxicity, the wide use of artemisinin effectively treats the otherwise drug-resistant parasites and helps many countries, including China, to eventually eradicate malaria. Here, we will first review the initial discovery of artemisinin, an extraordinary journey that was in stark contrast with many drugs in western medicine. We will then discuss how artemisinin and its derivatives could be repurposed to treat cancer, inflammation, immunoregulation-related diseases, and COVID-19. Finally, we will discuss the implications of the "artemisinin story" and how that can better guide the development of TCM today. We believe that artemisinin is just a starting point and TCM will play an even bigger role in healthcare in the 21st century.

Medicines for Malaria Venture COVID Box: a source for repurposing drugs with antifungal activity against human pathogenic fungi

BACKGROUND Treatment of mycoses is often ineffective, usually prolonged, and has some side effects. These facts highlight the importance of discovering new molecules to treat fungal infections. OBJECTIVES To search the Medicines for Malaria Venture COVID Box for drugs with antifungal activity. METHODS Fourteen human pathogenic fungi were tested against the 160 drugs of this collection at 1.0 µM concentration. We evaluated the ability of the drugs to impair fungal growth, their fungicidal nature, and morphological changes caused to cells. FINDINGS Thirty-four molecules (21.25%) presented antifungal activity. Seven are antifungal drugs and one is the agricultural fungicide cycloheximide. The other drugs with antifungal activity included antibiotics (n = 3), antimalarials (n = 4), antivirals (n = 2), antiparasitcs (n = 3), antitumor agents (n = 5), nervous system agents (n = 3), immunosuppressants (n = 3), antivomiting (n = 1), antiasthmatic (n = 1), and a genetic disorder agent (n = 1). Several of these drugs inhibited Histoplasma capsulatum and Paracoccidioides brasiliensis growth (15 and 20, respectively), while Fusarium solani was not affected by the drugs tested. Most drugs were fungistatic, but niclosamide presented fungicidal activity against the three dimorphic fungi tested. Cyclosporine affected morphology of Cryptococcus neoformans. MAIN CONCLUSIONS These drugs represent new alternatives to the development of more accessible and effective therapies to treat human fungal infections.

An overview of the anti-SARS-CoV-2 properties of Artemisia annua, its antiviral action, protein-associated mechanisms, and repurposing for COVID-19 treatment / 中西医结合学报

Artemisia annua and its phytocompounds have a rich history in the research and treatment of malaria, rheumatoid arthritis, systemic lupus erythematosus, and other diseases. Currently, the World Health Organization recommends artemisinin-based combination therapy as the first-line treatment for multi-drug-resistant malaria. Due to the various research articles on the use of antimalarial drugs to treat coronaviruses, a question is raised: would A. annua and its compounds provide anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) properties? PubMed/MEDLINE, Scopus, and Google Scholar were searched for peer-reviewed articles that investigated the antiviral effects and mechanisms of A. annua and its phytochemicals against SARS-CoVs. Particularly, articles that evidenced the herb's role in inhibiting the coronavirus-host proteins were favored. Nineteen studies were retrieved. From these, fourteen in silico molecular docking studies demonstrated potential inhibitory properties of artemisinins against coronavirus-host proteins including 3CL

Repurposing clinical drugs is a promising strategy to discover drugs against Zika virus infection / 医学前沿

Zika virus (ZIKV) is an emerging pathogen associated with neurological complications, such as Guillain-Barré syndrome in adults and microcephaly in fetuses and newborns. This mosquito-borne flavivirus causes important social and sanitary problems owing to its rapid dissemination. However, the development of antivirals against ZIKV is lagging. Although various strategies have been used to study anti-ZIKV agents, approved drugs or vaccines for the treatment (or prevention) of ZIKV infections are currently unavailable. Repurposing clinically approved drugs could be an effective approach to quickly respond to an emergency outbreak of ZIKV infections. The well-established safety profiles and optimal dosage of these clinically approved drugs could provide an economical, safe, and efficacious approach to address ZIKV infections. This review focuses on the recent research and development of agents against ZIKV infection by repurposing clinical drugs. Their characteristics, targets, and potential use in anti-ZIKV therapy are presented. This review provides an update and some successful strategies in the search for anti-ZIKV agents are given.

High-throughput screening identifies established drugs as SARS-CoV-2 PLpro inhibitors

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M

Spontaneous repositioning of posterior chamber intraocular lens: a mere coincidence? / Reposicionamento espontâneo de uma lente intraocular na câmara posterior: uma mera coincidência?

ABSTRACT Despite the recent developments in modern cataract surgery and the application of a vast array of new devices and machines, late in-the-bag intraocular lens dislocation remains a devastating, albeit rare, complication. Various nonsurgical and surgical techniques have been used to manage this complication. We report a case of spontaneous repositioning in the left eye of an anteriorly subluxated in-the-bag intraocular lens. The spontaneous repositioning may have been caused by antagonistic effects related to the topical administration of brimonidine and prednisolone. The dislocation was treated without aggressive manipulation or surgical intervention.

RESUMO Apesar dos recentes avanços na cirurgia moderna de catarata e da aplicação de uma ampla gama de novos dispositivos, o deslocamento tardio de uma lente intraocular dentro do saco capsular continua a ser uma complicação devastadora, ainda que rara. Várias técnicas cirúrgicas e não cirúrgicas têm sido usadas para tratar esta complicação. Este é o relato de um caso de reposicionamento espontâneo de uma lente intraocular sub-luxada anteriormente dentro do saco capsular do olho esquerdo. Este reposicionamento pode ter sido causado pelos efeitos opostos da aplicação tópica simultânea de brimonidina e prednisolona. O deslocamento foi tratado sem manipulação agressiva ou intervenção cirúrgica.

Mecanismo de Ação do Anti-hipertensivo Manidipino em Trypanosoma cruzi: Uma Abordagem de Reposicionamento de Fármaco / Mechanism of Action of the Antihypertensive Drug Manidipine in Trypanosoma cruzi: A Drug Repositioning Approach

A doença de Chagas (DC), também conhecida como tripanossomíase americana, afeta cerca de 6 a 7 milhões de pessoas em todo o mundo, com aproximadamente 70 milhões de pessoas em áreas de risco. Causada pelo parasita Trypanosoma cruzi, a DC é um problema de saúde pública, ocorrendo do sul dos Estados Unidos ao norte da Argentina. Considerando a falta de terapia eficaz e segura para o tratamento da DC, e baseado em um efeito letal do fármaco anti-hipertensivo manidipino, aprovado pela Food and Drug Administration (FDA), este fármaco foi avaliado in vitro contra as formas tripomastigotas (extracelulares) e amastigotas (intracelulares) de Trypanosoma cruzi. O perfil bioenergético de tripomastigotas de T. cruzi foi estudado na presença do fármaco manidipino, utilizando ensaios fluorimétricos e luminescentes. O manidipino mostrou uma elevada atividade antiparasitária, com valores de CE50 de 0,1 µM em amastigotas intracelulares, e 3 µM em tripomastigotas, resultando em um índice de seletividade em formas amastigotas intracelulares promissor de > 2.000. Utilizando análise por citometria de fluxo, o fármaco mostrou despolarização...(AU)

Chagas Disease (CD), also known as American trypanosomiasis affects about 6 to 7 million people worldwide, with approximately 70 million people in risk areas. Caused by the parasite Trypanosoma cruzi, CD is a public health problem, occurring from the southern United States to northern Argentina. Considering the lack of effective and safe therapy for the treatment of CD, and based on a specific biochemical effect of a approved drug by Food and Drug Administration (FDA), the antihypertensive drug manidipine was in vitro evaluated against the trypomastigotes (extracellular) and intracellular (amastigotes) of Trypanosoma cruzi. The bioenergetics of trypomastigotes was studied in the presence of the drug using fluorimetric and luminescent assays. Manidipine showed a potent antiparasitic activity, with IC50 values of 0.1 µM (intracellular amastigotes) and 3 µM (trypomastigotes), resulting in a promising selectivity index against intracellular amastigotes (>2.000). Using flow cytometry analysis, the drug showed depolarization of electric potential of the plasma membrane, with no alteration of the permeability. A decrease of the ATP levels suggested a bioenergetics alteration of the mitochondria, which was confirmed by depolarization of the mitochondrial membrane potential and increased levels of ROS. The antihypertensive manidipine showed for the first time a promising in vitro effectiveness against T. cruzi and may represent a candidate for future investigations in animal models. (AU)

COVID-19: molecular targets, drug repurposing and new avenues for drug discovery

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious infection that may break the healthcare system of several countries. Here, we aimed at presenting a critical view of ongoing drug repurposing efforts for COVID-19 as well as discussing opportunities for development of new treatments based on current knowledge of the mechanism of infection and potential targets within. Finally, we also discuss patent protection issues, cost effectiveness and scalability of synthetic routes for some of the most studied repurposing candidates since these are key aspects to meet global demand for COVID-19 treatment.

Clinical trials on drug repositioning for COVID-19 treatment / Ensayos clínicos de reposicionamiento de medicamentos para el tratamiento de la COVID-19 / Ensaios clínicos de reposicionamento de medicamentos para o tratamento do COVID-19

ABSTRACT The World Health Organization (WHO) was informed on December 2019 about a coronavirus pneumonia outbreak in Wuhan, Hubei province (China). Subsequently, on March 12, 2020, 125,048 cases and 4,614 deaths were reported. Coronavirus is an enveloped RNA virus, from the genus Betacoronavirus, that is distributed in birds, humans, and other mammals. WHO has named the novel coronavirus disease as COVID-19. More than 80 clinical trials have been launched to test coronavirus treatment, including some drug repurposing or repositioning for COVID-19. Hence, we performed a search in March 2020 of the clinicaltrials.gov database. The eligibility criteria for the retrieved studies were: contain a clinicaltrials.gov base identifier number; describe the number of participants and the period for the study; describe the participants' clinical conditions; and utilize interventions with medicines already studied or approved for any other disease in patients infected with the novel coronavirus SARS-CoV-2 (2019-nCoV). It is essential to emphasize that this article only captured trials listed in the clinicaltrials.gov database. We identified 24 clinical trials, involving more than 20 medicines, such as human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, methylprednisolone, bevacizumab, and traditional Chinese medicines (TCM). Although drug repurposing has some limitations, repositioning clinical trials may represent an attractive strategy because they facilitate the discovery of new classes of medicines; they have lower costs and take less time to reach the market; and there are existing pharmaceutical supply chains for formulation and distribution.(AU)

RESUMEN En diciembre de 2019 fue informado a la Organización Mundial de la Salud (OMS) un brote de neumonía por coronavirus en Wuhan, provincia de Hubei, China. Al 12 de marzo de 2020, se habían notificado 125 048 casos y 4 614 muertes. El coronavirus es un virus ARN envuelto del género Betacoronavirus distribuido en aves, seres humanos y otros mamíferos. La OMS ha denominado a la nueva enfermedad por coronavirus COVID-19. Se han puesto en marcha más de 80 ensayos clínicos para evaluar un tratamiento para el coronavirus, que incluyen algunos ensayos de reposicionamiento de medicamentos para la COVID-19. En marzo de 2020 se llevó a cabo una búsqueda de los ensayos clínicos registrados en la base de datos clinicaltrials.gov. Los criterios de elegibilidad para los estudios recuperados fueron tener un número de identificación de la base de datos clinicaltrials.gov; describir el número de participantes y el período del estudio; describir las condiciones clínicas de los participantes; y emplear intervenciones con medicamentos ya estudiados o aprobados para cualquier otra enfermedad en pacientes infectados con el nuevo coronavirus SARS-CoV-2 (2019-nCoV). Es esencial destacar que este artículo solo recoge los ensayos que figuran en la base de datos clinicaltrials. gov. Se identificaron 24 ensayos clínicos relacionados con más de 20 medicamentos, como inmunoglobulina humana, interferones, cloroquina, hidroxicloroquina, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, metilprednisolona, bevacizumab y medicina tradicional china. Aunque el reposicionamiento de medicamentos tiene algunas limitaciones, el reposicionamiento de los ensayos clínicos puede representar una estrategia atractiva porque facilita el descubrimiento de nuevas clases de medicamentos; estos tienen costos más bajos y tardan menos en llegar al mercado; y existen cadenas de suministro farmacéutico que apoyan la formulación y la distribución.(AU)

RESUMO A Organização Mundial da Saúde (OMS) foi informada, em dezembro de 2019, sobre um surto de pneumonia por coronavírus em Wuhan, província de Hubei (China). Posteriormente, em 12 de março de 2020, 125 048 casos e 4 614 mortes haviam sido registrados. O coronavírus é um vírus RNA envelopado do gênero Betacoronavírus, distribuído em aves e em humanos e outros mamíferos. A OMS designou a nova doença por coronavírus como COVID-19. Mais de 80 ensaios clínicos foram iniciados para testar tratamentos para o coronavírus, incluindo alguns de reposicionamento de medicamentos para o COVID-19. Assim, em março de 2020 realizou-se uma busca na base de dados clinicaltrials.gov. Os critérios de elegibilidade para os estudos recuperados foram: conter o número identificador da base de dados clinicaltrials.gov; descrever o número de participantes e o período do estudo; descrever as condições clínicas dos participantes; e utilizar intervenções para tratamento de doentes infectados com o novo coronavírus SARS-CoV-2 (2019-nCoV) com medicamentos já estudados ou aprovados para qualquer outra doença. É essencial salientar que este artigo apenas capturou ensaios listados na base de dados clinicaltrials.gov. Foram identificados 24 ensaios clínicos envolvendo mais de 20 medicamentos, tais como imunoglobulina humana, interferons, cloroquina, hidroxicloroquina, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, metilprednisolona, bevacizumabe e medicamentos chineses tradicionais. Embora o reposicionamento de medicamentos tenha algumas limitações, os ensaios clínicos de reposicionamento podem representar uma estratégia atraente, porque facilitam a descoberta de novas classes de medicamentos, têm custos mais baixos, levam menos tempo para chegar ao mercado e se beneficiam de cadeias de fornecimento farmacêutico já existentes para formulação e distribuição.(AU)

In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy / 中国结合医学杂志

OBJECTIVE@#To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening.@*METHODS@#The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper.@*RESULTS@#It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score.@*CONCLUSIONS@#A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.

In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy / 中国结合医学杂志

OBJECTIVE@#To select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening.@*METHODS@#The three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper.@*RESULTS@#It was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score.@*CONCLUSIONS@#A class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.

Estudo de alterações celulares e moleculares em Leishmania (leishmania) infantum tratada com fármacos anti-histamínicos / Study of cellular and molecular changes in Leishmania (leishmania) infantum treated with antihistamine drugs

A leishmaniose visceral (LV) é uma doença infecciosa sistêmica, causada pelos parasitos protozoários do gênero Leishmania, endêmica em países tropicais e subtropicais. Por acometer principalmente populações de baixa renda em países em desenvolvimento e subdesenvolvidos, a leishmaniose se encaixa no perfil das doenças negligenciadas, em razão de seu baixo retorno financeiro para a indústria farmacêutica. Devido ao alto custo, restrições e efeitos colaterais dos atuais fármacos utilizados na terapêutica da leishmaniose, há a real necessidade de identificar e desenvolver novas alternativas como a de reposicionamento de fármacos, que se trata de uma nova indicação terapêutica para um fármaco já disponibilizado no mercado. Desta forma, o objetivo deste trabalho foi avaliar a atividade antileishmania de fármacos anti-histamínicos e identificar marcadores celulares e moleculares relacionados à resposta terapêutica, usando um sistema de infecção in vitro. Foram realizados em Leishmania (Leishmania) intantum: i) a triagem de quatro fármacos anti-histamínicos, sendo eles: cetirizina (CTZ), ciproeptadina (CPH), fexofenadina (FXF) e meclizina (MCZ); ii) o estudo das alterações celulares e moleculares com o fármaco cinarizina (CNZ) e os que apresentaram atividade contra a forma amastigota. Para isto, foi feito estudos de concentração efetiva 50% (CE50) em promastigota e amastigota de L. (L.) infantum, concentração citotóxica 50% (CC50) em células de mamífero e após foram analisadas a permeabilidade de membrana plasmática, o potencial de membrana mitocondrial, a produção de espécies reativas de oxigênio (ERO) e a produção de tióis por meio de ensaios fluorimétricos e as ultra-estruturas celulares por microscopia eletrônica de transmissão e o perfil de expressão gênica por qPCR. Os resultados mostraram que CPH e MCZ apresentaram atividade antileishmania contra promastigotas, com CE50 de 7 e 22 µM, respectivamente. CPH e MCZ eliminaram os amastigotas, com CE50 de 30 e 35 µM, respectivamente. Os fármacos CTZ e FXF não apresentaram atividade contra ambas as formas do parasito. CNZ, CPH e MCZ provocaram em promastigota: i) alteração na permeabilidade da membrana plasmática; ii) despolarização do potencial de membrana mitocondrial, provocando danos celulares associados com o sistema bioenergético; iii) alteração no perfil de expressão gênica de 11 genes que codificam para diferentes funções celulares. Estes dados, além de apresentarem resultados direto para o tratamento das leishmanioses, com o desenvolvimento de novas alternativas, apresenta um grande potencial como sistema de avaliação de resposta terapêutica de vários tipos de fármacos.

Current state and outlook for drug repositioning anticipated in the field of ovarian cancer / 부인종양

Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti-vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention.

Análise estrutural e molecular de aspártico peptidases em Trypanosoma cruzi / Structural and molecular analysis of aspartic peptidases in Trypanosoma cruzi

As peptidases do Trypanosoma cruzi, agente etiológico da doença de Chagas, são importantes fatores de virulência e alvo para quimioterapia. As aspártico peptidases ainda não foram caracterizadas neste parasito, porém, inibidores de aspártico peptidase do vírus da imunodeficiência humana (IPs-HIV) tem ação tripanocida. O objetivo desse trabalho é caracterizar as aspártico peptidases em T. cruzi. Através de análises in silico, identificamos que dos três genes anotados como aspártico peptidases, dois genes, Presenilina símile (PS) e Peptidase Peptideo Sinal símile (PPs símile), compartilham o mesmo domínio proteico, o domínio PSN (Presenilin/Signalpeptideo peptidase familly). A presenilina símile de T. cruzi possui nove domínios transmembranas e uma ampla dobra entre os domínios seis e sete, que resulta em uma espaçosa região hidrofóbica, o que indica que a presenilina símile de T. cruzi possui uma estrutura secundária altamente similar e indispensável para origem de uma presenilina ativa. A PPs símile de T. cruzi possui uma sequência de múltiplas passagens pela membrana, e revela uma grande semelhança com as presenilinas, incluindo a conservação do seu domínio. O gene anotado como DNA damage inducible Ddi 1 (Ddi 1 símile) possui o domínio retroviral peptidase (RVP), característico dessa família de peptidases. A Ddi 1 símile de T. cruzi possui o domínio UBL (ubiquitina símile)

A modelagem molecular do domínio (RVP) da proteína Ddi 1 símile de T. cruzi mostrou que esse domínio forma um homodímero que é característico das aspártico peptidases da família A2, e que cada monômero possui a sequência conservada Asp-Ser-Gly-Ala. O estudo de atração molecular (docking) mostrou uma diferente afinidade dos IPs-HIV pelo sítio ativo do domínio RVP da proteína, enquanto que pepstatina A e benzonidazol, controles positivo e negativo, apresentaram os melhores e piores índices de docking, respectivamente. Uma proteína heteróloga Ddi 1 símile foi expressa em Escherichia coli e purificada. A enzima purificada não apresentou atividade proteolítica contra substrato fluorogênico específico para Catepsina D, indicando que alterações estruturais importantes ocorreram na enzima heteróloga. O extrato total de E. coli, rico na proteína induzida, não foi capaz de degradar soro albumina bovina. Os IPs-HIV possuem ação tripanocida, porém o alvo intracelular e mecanismo de ação ainda não estão elucidados. Esse trabalho traz importantes contribuições para este campo, e abre perspectivas de explorar esta enzima para o desenho de novos fármacos, ou para modificações químicas nos IPs-HIV disponíveis para aumentar sua especificidade e potência. (AU)

A review of computational drug repurposing

Although sciences and technology have progressed rapidly, de novo drug development has been a costly and time-consuming process over the past decades. In view of these circumstances, ‘drug repurposing’ (or ‘drug repositioning’) has appeared as an alternative tool to accelerate drug development process by seeking new indications for already approved drugs rather than discovering de novo drug compounds, nowadays accounting for 30% of newly marked drugs in the U.S. In the meantime, the explosive and large-scale growth of molecular, genomic and phenotypic data of pharmacological compounds is enabling the development of new area of drug repurposing called computational drug repurposing. This review provides an overview of recent progress in the area of computational drug repurposing. First, it summarizes available repositioning strategies, followed by computational methods commonly used. Then, it describes validation techniques for repurposing studies. Finally, it concludes by discussing the remaining challenges in computational repurposing.

Guanabenz Acetate Induces Endoplasmic Reticulum Stress–Related Cell Death in Hepatocellular Carcinoma Cells

BACKGROUND: Development of chemotherapeutics for the treatment of advanced hepatocellular carcinoma (HCC) has been lagging. Screening of candidate therapeutic agents by using patient-derived preclinical models may facilitate drug discovery for HCC patients. METHODS: Four primary cultured HCC cells from surgically resected tumor tissues and six HCC cell lines were used for high-throughput screening of 252 drugs from the Prestwick Chemical Library. The efficacy and mechanisms of action of the candidate anti-cancer drug were analyzed via cell viability, cell cycle assays, and western blotting. RESULTS: Guanabenz acetate, which has been used as an antihypertensive drug, was screened as a candidate anti-cancer agent for HCC through a drug sensitivity assay by using the primary cultured HCC cells and HCC cell lines. Guanabenz acetate reduced HCC cell viability through apoptosis and autophagy. This occurred via inhibition of growth arrest and DNA damage-inducible protein 34, increased phosphorylation of eukaryotic initiation factor 2α, increased activating transcription factor 4, and cell cycle arrest. CONCLUSIONS: Guanabenz acetate induces endoplasmic reticulum stress–related cell death in HCC and may be repositioned as an anti-cancer therapeutic agent for HCC patients.

PharmacoNER Tagger: a deep learning-based tool for automatically finding chemicals and drugs in Spanish medical texts

Automatically detecting mentions of pharmaceutical drugs and chemical substances is key for the subsequent extraction of relations of chemicals with other biomedical entities such as genes, proteins, diseases, adverse reactions or symptoms. The identification of drug mentions is also a prior step for complex event types such as drug dosage recognition, duration of medical treatments or drug repurposing. Formally, this task is known as named entity recognition (NER), meaning automatically identifying mentions of predefined entities of interest in running text. In the domain of medical texts, for chemical entity recognition (CER), techniques based on hand-crafted rules and graph-based models can provide adequate performance. In the recent years, the field of natural language processing has mainly pivoted to deep learning and state-of-the-art results for most tasks involving natural language are usually obtained with artificial neural networks. Competitive resources for drug name recognition in English medical texts are already available and heavily used, while for other languages such as Spanish these tools, although clearly needed were missing. In this work, we adapt an existing neural NER system, NeuroNER, to the particular domain of Spanish clinical case texts, and extend the neural network to be able to take into account additional features apart from the plain text. NeuroNER can be considered a competitive baseline system for Spanish drug and CER promoted by the Spanish national plan for the advancement of language technologies (Plan TL).