Remdesivir for the treatment of COVID-19

Grundeis, Felicitas; Ansems, Kelly; Dahms, Karolina; Thieme, V.; Metzendorf, Maria‐Inti; Skoetz, Nicole; Benstoem, Carina; Mikołajewska, Agata; Griesel, Mirko; Fichtner, Falk; Stegemann, Miriam

doi:10.1002/14651858.cd014962.pub2

Cited by 48 publications

(50 citation statements)

References 117 publications

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“…Currently, there are two clinically approved antiviral drugs widely used for the management of COVID-19 symptoms in mild-to-severe cases, Paxlovid™ (nirmatrelvir and ritonavir) and remdesivir [Reis et al, 2022; Eastman et al, 2020; Grundeis et al, 2023]. Despite their approval, double-blind and placebo-controlled studies with expansive and diverse subject groups remain limited, and many intervention methods were approved for use under emergency need; thus, their long-term effects and efficacy are not yet well-understood [Reis et al, 2022; Grundeis et al, 2023]. Nirmatrelvir irreversibly inhibits SARS-CoV-2 M pro by forming a covalent bond with its catalytic cysteine [Li et al, 2022].…”

Section: Discussionmentioning

confidence: 99%

Dual inhibition of coronavirus M^proand PL^proenzymes by phenothiazines and their antiviral activity

Forrestall,

Pringle,

Sands

et al. 2023

Preprint

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Coronavirus (CoV) replication requires efficient cleavage of viral polyproteins into an array of non-structural proteins involved in viral replication, organelle formation, viral RNA synthesis, and host shutoff. Human CoVs (HCoVs) encode two viral cysteine proteases, main protease (Mpro) and papain-like protease (PLpro), that mediate polyprotein cleavage. Using a structure-guided approach, a phenothiazine urea derivative that inhibits both SARS-CoV-2 Mproand PLproprotease activityin vitrowas identified.In silicodocking studies also predicted binding of the phenothiazine to the active sites of Mproand PLprofrom distantly related alphacoronavirus, HCoV-229E (229E) and the betacoronavirus, HCoV-OC43 (OC43). The lead phenothiazine urea derivative displayed broad antiviral activity against all three HCoVs tested in cell culture infection models. It was further demonstrated that the compound inhibited 229E and OC43 at an early stage of viral replication, with diminished formation of viral replication organelles and the RNAs that are made within them, as expected following viral protease inhibition. These observations suggest that the phenothiazine urea derivative inhibits viral replication and may broadly inhibit proteases of diverse coronaviruses.Graphical AbstractHighlightsCoronavirus cysteine proteases Mproand PLproare targets for novel antiviral agentsPhenothiazine ureas inhibit SARS-CoV-2 Mproand PLproprotease activitySome phenothiazine ureas inhibit replication of diverse coronaviruses with minimal cytotoxicityPhenothiazine ureas inhibit early stages of coronavirus replication consistent with failure of viral polyprotein cleavage

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Section: Discussionmentioning

confidence: 99%

Dual inhibition of coronavirus M^proand PL^proenzymes by phenothiazines and their antiviral activity

Forrestall,

Pringle,

Sands

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 pathogen, has resulted in a worldwide pandemic. Researchers have made extensive efforts ( Grundeis et al , 2023 ; Hassanipour et al , 2021 ; Reis et al , 2022 ; Rosas et al , 2021 ; Temple et al , 2021 ) to repurpose existing drugs to treat COVID-19. Remdesivir was the first repurposed antiviral drug that was approved by the United States Food and Drug Administration for the treatment of COVID-19.…”

Section: Use Casesmentioning

confidence: 99%

ARAX: a graph-based modular reasoning tool for translational biomedicine

Glen

Mendoza

et al. 2023

Bioinformatics

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Motivation With the rapidly growing volume of knowledge and data in biomedical databases, improved methods for knowledge-graph-based computational reasoning are needed in order to answer translational questions. Previous efforts to solve such challenging computational reasoning problems have contributed tools and approaches, but progress has been hindered by the lack of an expressive analysis workflow language for translational reasoning and by the lack of a reasoning engine—supporting that language—that federates semantically integrated knowledge-bases. Results We introduce ARAX, a new reasoning system for translational biomedicine that provides a web browser user interface and an application programming interface. ARAX enables users to encode translational biomedical questions and to integrate knowledge across sources to answer the user’s query and facilitate exploration of results. For ARAX, we developed new approaches to query planning, knowledge-gathering, reasoning, and result ranking and dynamically integrate knowledge providers for answering biomedical questions. To illustrate ARAX’s application and utility in specific disease contexts, we present several use-case examples. Availability and Implementation The source code and technical documentation for building the ARAX server-side software and its built-in knowledge database are freely available online (https://github.com/RTXteam/RTX). We provide a hosted ARAX service with a web browser interface at arax.rtx.ai and a web application programming interface (API) endpoint at arax.rtx.ai/api/arax/v1.3/ui/. Supplementary information Supplementary data are available at Bioinformatics online.

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“…36,37 Remdesivir has been suggested as a treatment for respiratory coronavirus diseases in humans, most notably COVID-19 due to SARS-CoV-2, although clear evidence for a beneficial effect in humans is lacking and the results of different studies are contradictory. 38 Remdesivir has also been considered for FIP treatment in cats, 39 but its safety and efficacy have not been established in controlled peer-reviewed publications. However, favourable reports of the use of remdesivir to treat FIP in small numbers of cats have emerged, 40 –43 including the use of a regulated veterinary compounded ‘Specials’ product of injectable remdesivir (of known composition, as outlined above for GS-441524) legally available for cats in Australia (since November 2020), the UK (since August 2021) and some other countries (dependent on importation regulations, similar to GS-441524).…”

Section: Introductionmentioning

confidence: 99%

Retrospective study and outcome of 307 cats with feline infectious peritonitis treated with legally sourced veterinary compounded preparations of remdesivir and GS-441524 (2020–2022)

Taylor,

Coggins,

Barker

et al. 2023

Journal of Feline Medicine and Surgery

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Objectives Feline infectious peritonitis (FIP) is a serious disease that arises due to feline coronavirus infection. The nucleoside analogues remdesivir and GS-441524 can be effective in its treatment, but most studies have used unregulated products of unknown composition. The aim of the present study was to describe the treatment of FIP using legally sourced veterinary-prescribed regulated veterinary compounded products containing known amounts of remdesivir (injectable) or GS-441524 (oral tablets). Methods Cats were recruited via email advice services, product sales contacts and study publicity. Cats were excluded if they were deemed unlikely to have FIP, were not treated exclusively with the veterinary compounded products, or if there was a lack of cat and/or treatment (including response) data. Extensive cat and treatment data were collected. Results Among the 307 cats recruited, the predominant type of FIP was most commonly abdominal effusive (49.5%) and then neurological (14.3%). Three treatment protocols were used; remdesivir alone (33.9%), remdesivir followed by GS-441524 (55.7%) and GS-441524 alone (10.4%). The median (range) initial treatment period duration and longest follow-up time point after starting treatment were 84 (1–330) days and 248 (1–814) days, respectively. The most common side effect was injection pain (in 47.8% of those given subcutaneous remdesivir). Of the 307 cats, 33 (10.8%) relapsed, 15 (45.5%) during and 18 (54.5%) after the initial treatment period. At the longest follow-up time point after completion of the initial treatment period, 84.4% of cats were alive. The cats achieving a complete response within 30 days of starting treatment were significantly more likely to be alive at the end of the initial treatment period than those cats that did not. Conclusions and relevance Legally sourced remdesivir and GS-441524 products, either alone or used sequentially, were very effective in the treatment of FIP in this group of cats. Variable protocols precluded statistical comparison of treatment regimens.

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Remdesivir for the treatment of COVID-19

Cited by 48 publications

References 117 publications

Dual inhibition of coronavirus M^proand PL^proenzymes by phenothiazines and their antiviral activity

Dual inhibition of coronavirus M^proand PL^proenzymes by phenothiazines and their antiviral activity

ARAX: a graph-based modular reasoning tool for translational biomedicine

Retrospective study and outcome of 307 cats with feline infectious peritonitis treated with legally sourced veterinary compounded preparations of remdesivir and GS-441524 (2020–2022)

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Remdesivir for the treatment of COVID-19

Cited by 48 publications

References 117 publications

Dual inhibition of coronavirus Mproand PLproenzymes by phenothiazines and their antiviral activity

Dual inhibition of coronavirus Mproand PLproenzymes by phenothiazines and their antiviral activity

ARAX: a graph-based modular reasoning tool for translational biomedicine

Retrospective study and outcome of 307 cats with feline infectious peritonitis treated with legally sourced veterinary compounded preparations of remdesivir and GS-441524 (2020–2022)

Contact Info

Product

Resources

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Dual inhibition of coronavirus M^proand PL^proenzymes by phenothiazines and their antiviral activity

Dual inhibition of coronavirus M^proand PL^proenzymes by phenothiazines and their antiviral activity