Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches

Batalha, Pedro N.; Forezi, Luana da S. M.; Lima, Carolina G. S.; Pauli, Fernanda P.; Boechat, Fernanda da Costa Santos; Souza, Maria Cecília B. V. de; Cunha, Anna C.; Ferreira, Vı́tor F.; Silva, Fernando de Carvalho da

doi:10.1016/j.bioorg.2020.104488

Cited by 28 publications

(17 citation statements)

References 254 publications

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“…constantly evolving SARS-CoV-2 variants. As a repurposing candidate, disulfiram has particular advantages given its low cost, both in production and distribution, and favorable effect profile (2,18).…”

Section: Discussionmentioning

confidence: 99%

“…Given the urgent medical need, additional clinical trials in uninfected populations as well as in early and late COVID-19 disease are highly desirable with the aim of testing the impact that disulfiram may have across the entire COVID-19 continuum, from infection to disease progression and including the current and constantly evolving SARS-CoV-2 variants. As a repurposing candidate, disulfiram has particular advantages given its low cost, both in production and distribution, and favorable effect profile (2,18).…”

Section: Discussionmentioning

confidence: 99%

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Disulfiram associated with lower risk of Covid-19: a retrospective cohort study

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Bell

Shen

et al. 2021

Preprint

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In the global COVID-19 pandemic, there is a substantial need for effective, low-cost therapeutics. We investigated the potential effects of disulfiram on the incidence and outcomes of COVID-19 in an observational study in a large database of US Veterans Administration clinical records, the VA Corporate Data Warehouse (CDW). The study is motivated by the unique properties of disulfiram, which has been used as an anti-alcoholism drug since 1948, is non-toxic, easy to manufacture and inexpensive. Disulfiram reduces hyperinflammation in mammalian cells by inhibition of the gasdermin D pore. In a mouse model of sepsis, disulfiram reduced inflammatory cytokines and mortality. Disulfiram also is a low micromolar inhibitor of the Mpro and PLpro viral proteases of SARS-CoV-2. To investigate the potential effects of disulfiram on the incidence and severity of COVID-19, we carried out an epidemiological study in the CDW. The VA dataset used has 944,127 patients tested for SARS-Cov-2, 167,327 with a positive test, and 2,233 on disulfiram, of which 188 had a positive SARS-Cov-2 test. A multivariable Cox regression adjusted for age, gender, race/ethnicity, region, a diagnosis of alcohol use disorders, and Charlson comorbidity score revealed a reduced incidence of COVID-19 with disulfiram use with a hazard ratio of 0.66 and 95% confidence interval of 0.57 to 0.76 (P < 0.001). There were no deaths among the 188 SARS-Cov-2 positive patients treated with disulfiram. The expected number of deaths would have been 5-6 according to the 3% death rate among the untreated (P-value 0.03). Our finding of a lower hazard ratio and less severe outcomes for COVID-19 in patients treated with disulfiram compared to those not treated is a statistical association and does not prove any causative effect of disulfiram. However, the results of this study suggest that there is a pharmacological contribution to the reduced incidence and severity of COVID-19 with the use of disulfiram. Given the known anti-inflammatory and viral anti-protease effects of disulfiram, it is reasonable and urgent to initiate accelerated clinical trials to assess whether disulfiram reduces SARS-CoV-2 infection, disease severity and death.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disulfiram associated with lower risk of Covid-19: a retrospective cohort study

Fillmore

Bell

Shen

et al. 2021

Preprint

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“…Because of the outbreak of SARS-CoV-2, several medicines are being repurposed (repositioned drugs); for example, ribavirin, lopinavir, ritonavir, chloroquine, and rapamycin, and have been used as part of the treatment or as self-medication (especially in places where the healthcare systems are not adequate) constituting one of the most common emerging contaminants in aquatic systems ( Kumari and Kumar, 2021 ; Usman et al, 2020 ) causing serious damage to aquatic compartments and biota ( Table 1 ). This is the case of antiviral compounds, anticancer drugs, antihypertensive drugs, immunosuppressants, antipsychotics and antihistamines, antifungal agents, antibacterial agents, and therapeutic antibodies ( Batalha et al, 2021 ). Here it should be noted that, antiviral and antibiotics drugs have to be specially mentioned since their use in the past years has been increased and with that, the antiviral and antibiotic resistance as already mentioned( Cela-Dablanca et al, 2021 ).…”

Section: Emerging Contaminants Produced By the Treatment And Fight Against Sars-cov-2mentioning

confidence: 99%

Emerging contaminants, SARS-COV-2 and wastewater treatment plants, new challenges to confront: A short review

Pacheco

Hilares

Andrade

et al. 2021

Bioresource Technology Reports

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The current pandemic caused by SARS-CoV-2 has put public health at risk, being wastewater-based epidemiology (WBE) a potential tool in the detection, prevention, and treatment of present and possible future outbreaks, since this virus enters wastewater through various sources such as feces, vomit, and sputum. Thus, advanced technologies such as advanced oxidation processes (AOP), membrane technology (MT) are identified through a systematic literature review as an alternative option for the destruction and removal of emerging contaminants (drugs and personal care products) released mainly by infected patients. The objectives of this review are to know the implications that the new COVID-19 outbreak is generating and will generate in water compartments, as well as the new challenges faced by wastewater treatment plants due to the change in a load of contaminants and the solutions proposed based on the aforementioned technologies to be applied to preserve public health and the environment.

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“…In the light of this difficulty, drug repurposing presents a very practical strategy for drug development against SARS-CoV-2. [4][5][6] Drug repurposing is based on the use of already approved drugs for the treatment of other diseases, in this case COVID-19, bypassing the clinical trials and regulatory stages associated with the development of a new drug. The reduction in the number of required steps for approval potentially reduces the time required for the drug to reach the market.…”

Section: Introductionmentioning

confidence: 99%

“…The reduction in the number of required steps for approval potentially reduces the time required for the drug to reach the market. [4][5][6] As a consequence, many repurposed drugs are currently in clinical trials, although there is not yet any approved antiviral medication against SARS-CoV-2.…”

Section: Introductionmentioning

confidence: 99%

Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking

Ribone

Paz

Abrams

et al. 2021

Preprint

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Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such high-throughput 1 repurposing screens have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking protocol that uses all-atom protein structures and a combination of docking methods to rankorder targets for each of several existing drugs for which a plurality of recent highthroughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with known drug-target pairs, including both non-antiviral and antiviral compounds. We subjected 152 distinct drugs potentially suitable for repurposing to the inverse docking procedure. The most common preferential targets were the human enzymes TMPRSS2 and PIKfyve, followed by the viral enzymes Helicase and PLpro.All compounds that selected TMPRSS2 are known serine protease inhibitors, and those that selected PIKfyve are known tyrosine kinase inhibitors. Detailed structural analysis of the docking poses revealed important insights into why these selections arose, and could potentially lead to more rational design of new drugs against these targets.

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Drug repurposing for the treatment of COVID-19: Pharmacological aspects and synthetic approaches

Cited by 28 publications

References 254 publications

Disulfiram associated with lower risk of Covid-19: a retrospective cohort study

Disulfiram associated with lower risk of Covid-19: a retrospective cohort study

Emerging contaminants, SARS-COV-2 and wastewater treatment plants, new challenges to confront: A short review

Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking

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