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1.
PLoS One ; 16(10): e0258292, 2021.
Article in English | MEDLINE | ID: covidwho-1480450

ABSTRACT

Chagas disease is a neglected illness caused by Trypanosoma cruzi and its treatment is done only with two drugs, nifurtimox and benznidazole. However, both drugs are ineffective in the chronic phase, in addition to causing serious side effects. This context of therapeutic limitation justifies the continuous research for alternative drugs. Here, we study the in vitro trypanocidal effects of the non-steroidal anti-inflammatory drug nimesulide, a molecule that has in its chemical structure a toxicophoric nitroaromatic group (NO2). The set of results obtained in this work highlights the potential for repurposing nimesulide in the treatment of this disease that affects millions of people around the world.


Subject(s)
Chagas Disease/drug therapy , Chagas Disease/parasitology , Drug Repositioning , Sulfonamides/therapeutic use , Trypanosoma cruzi/physiology , Animals , Cell Death/drug effects , Cell Survival/drug effects , Life Cycle Stages/drug effects , Mice, Inbred BALB C , Parasites/drug effects , Sulfonamides/chemistry , Sulfonamides/pharmacology , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/growth & development , Trypanosoma cruzi/ultrastructure
2.
Molecules ; 25(21)2020 Nov 07.
Article in English | MEDLINE | ID: covidwho-1305742

ABSTRACT

Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite's life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.


Subject(s)
Antimalarials/pharmacology , Drug Discovery/trends , Malaria/drug therapy , Plasmodium/drug effects , Protein Kinase Inhibitors/pharmacology , Animals , Calcium/metabolism , Casein Kinase I/metabolism , Culicidae , Drug Design , Drug Resistance , Glycogen Synthase Kinase 3/metabolism , Humans , Imidazoles/pharmacology , Inhibitory Concentration 50 , Life Cycle Stages/drug effects , MAP Kinase Signaling System , Phosphotransferases/chemistry , Plasmodium/enzymology , Pyridines/pharmacology
3.
Viruses ; 13(4)2021 04 09.
Article in English | MEDLINE | ID: covidwho-1178434

ABSTRACT

Therapeutic options for coronaviruses remain limited. To address this unmet medical need, we screened 5406 compounds, including United States Food and Drug Administration (FDA)-approved drugs and bioactives, for activity against a South Korean Middle East respiratory syndrome coronavirus (MERS-CoV) clinical isolate. Among 221 identified hits, 54 had therapeutic indexes (TI) greater than 6, representing effective drugs. The time-of-addition studies with selected drugs demonstrated eight and four FDA-approved drugs which acted on the early and late stages of the viral life cycle, respectively. Confirmed hits included several cardiotonic agents (TI > 100), atovaquone, an anti-malarial (TI > 34), and ciclesonide, an inhalable corticosteroid (TI > 6). Furthermore, utilizing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we tested combinations of remdesivir with selected drugs in Vero-E6 and Calu-3 cells, in lung organoids, and identified ciclesonide, nelfinavir, and camostat to be at least additive in vitro. Our results identify potential therapeutic options for MERS-CoV infections, and provide a basis to treat coronavirus disease 2019 (COVID-19) and other coronavirus-related illnesses.


Subject(s)
Antiviral Agents/pharmacology , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/isolation & purification , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , COVID-19/drug therapy , Coronavirus Infections/virology , Drug Approval , Drug Evaluation, Preclinical , Drug Repositioning , Drug Synergism , Humans , Life Cycle Stages/drug effects , Middle East Respiratory Syndrome Coronavirus/growth & development , Small Molecule Libraries/pharmacology
4.
Nature ; 593(7859): 418-423, 2021 05.
Article in English | MEDLINE | ID: covidwho-1137788

ABSTRACT

The COVID-19 pandemic is the third outbreak this century of a zoonotic disease caused by a coronavirus, following the emergence of severe acute respiratory syndrome (SARS) in 20031 and Middle East respiratory syndrome (MERS) in 20122. Treatment options for coronaviruses are limited. Here we show that clofazimine-an anti-leprosy drug with a favourable safety profile3-possesses inhibitory activity against several coronaviruses, and can antagonize the replication of SARS-CoV-2 and MERS-CoV in a range of in vitro systems. We found that this molecule, which has been approved by the US Food and Drug Administration, inhibits cell fusion mediated by the viral spike glycoprotein, as well as activity of the viral helicase. Prophylactic or therapeutic administration of clofazimine in a hamster model of SARS-CoV-2 pathogenesis led to reduced viral loads in the lung and viral shedding in faeces, and also alleviated the inflammation associated with viral infection. Combinations of clofazimine and remdesivir exhibited antiviral synergy in vitro and in vivo, and restricted viral shedding from the upper respiratory tract. Clofazimine, which is orally bioavailable and comparatively cheap to manufacture, is an attractive clinical candidate for the treatment of outpatients and-when combined with remdesivir-in therapy for hospitalized patients with COVID-19, particularly in contexts in which costs are an important factor or specialized medical facilities are limited. Our data provide evidence that clofazimine may have a role in the control of the current pandemic of COVID-19 and-possibly more importantly-in dealing with coronavirus diseases that may emerge in the future.


Subject(s)
Antiviral Agents/pharmacology , Clofazimine/pharmacology , Coronavirus/classification , Coronavirus/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Biological Availability , Cell Fusion , Cell Line , Clofazimine/pharmacokinetics , Clofazimine/therapeutic use , Coronavirus/growth & development , Coronavirus/pathogenicity , Cricetinae , DNA Helicases/antagonists & inhibitors , Drug Synergism , Female , Humans , Life Cycle Stages/drug effects , Male , Mesocricetus , Pre-Exposure Prophylaxis , SARS-CoV-2/growth & development , Species Specificity , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Transcription, Genetic/drug effects , Transcription, Genetic/genetics
5.
Cell Signal ; 74: 109721, 2020 10.
Article in English | MEDLINE | ID: covidwho-665126

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, single-stranded RNA virus that causes the potentially lethal Covid-19 respiratory tract infection. It does so by binding to host cell angiotensin converting enzyme 2 (ACE2) receptors, leading to endocytosis with the receptor, and subsequently using the host cell's machinery to replicate copies of itself and invade new cells. The extent of the spread of infection in the body is dependent on the pattern of ACE2 expression and overreaction of the immune system. Additionally, by inducing an imbalance in the renin-angiotensin-aldosterone system (RAAS) and the loss of ACE2 would favour the progression of inflammatory and thrombotic processes in the lungs. No drug or vaccine has yet been approved to treat human coronaviruses. Hundreds of clinical trials on existing approved drugs from different classes acting on a multitude of targets in the virus life cycle are ongoing to examine potential effectiveness for the prevention and treatment of the infection. This review summarizes the SARS-CoV-2 virus life cycle in the host cell and provides a biological and pathological point of view for repurposed and experimental drugs for this novel coronavirus. The viral life cycle provides potential targets for drug therapy.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/metabolism , Coronavirus Infections/drug therapy , Drug Repositioning/methods , Life Cycle Stages/drug effects , Molecular Targeted Therapy/methods , Pneumonia, Viral/drug therapy , Angiotensin-Converting Enzyme 2 , Betacoronavirus/chemistry , COVID-19 , Coronavirus Infections/prevention & control , Coronavirus Infections/virology , Humans , Pandemics/prevention & control , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/prevention & control , Pneumonia, Viral/virology , Renin-Angiotensin System/drug effects , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism , Viral Vaccines/immunology , Virus Internalization/drug effects , Virus Replication/drug effects
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