Adaptive Mutation in the Main Protease Cleavage Site of Feline Coronavirus Renders the Virus More Resistant to Main Protease Inhibitors

Jiao, Zhe; Yan, Yuanyuan; Chen, Yixi; Wang, Gang; Wang, Xiaowei; Li, Lisha; Yang, Mengfang; Hu, Xiaoshuai; Guo, Yilin; Shi, Yuejun; Peng, Guiqing

doi:10.1128/jvi.00907-22

Cited by 10 publications

(14 citation statements)

References 59 publications

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“…Potential viral resistance has not only been recognized for paxlovid's M pro -active ingredient nirmatrelvir but also for other late-stage M pro antivirals such as GC376 and boceprevir. In fact, a study by Peng and co-workers investigated the development of resistance in a feline coronavirus (FIPV) under pressure from GC376 and found that a mutation in nsp12 of its main protease rendered the enzyme up to three times less susceptible for the inhibitor [109]. Encouraging data from cell culture studies hint that GC376 performs efficiently against M pro 's from SARS-CoV-2 and various seasonal coronaviruses (NL63, 229E, and OC43), suggesting beneficial inhibition promiscuity of this drug that can be used as a basis for future structure development and antiviral testing [110].…”

Section: Inhibitors In Action-drug Performance In the Clinicmentioning

confidence: 99%

SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Fischer

Feys

2023

Future Pharmacology

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While the COVID-19 pandemic seems to be on its decline, the unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not to be underestimated threat. These cases, along with pandemic preparedness, ask for an alert identification of new drugs and the optimization of existing drugs as therapeutic treatment options for this and potential future diseases. Mpro inhibitors were identified early on as potent drug candidates against coronaviruses, since they target viable processing machinery within the virus, i.e., the main protease that cleaves the polyproteins encoded by the viral RNA into functional proteins. Different strategies, including reversible and irreversible inhibition as well as allosteric inhibitors, mostly from drug repurposing endeavors, have been explored in the design of potent SARS-CoV-2 Mpro antivirals. Ambitious screening efforts have uttered an outstanding chemical and structural diversity, which has led to half a dozen lead compounds being currently in clinical trials and the emergency FDA approval of ritonavir-boosted nirmatrelvir as a COVID-19 therapeutic. This comprehensive analysis of the achieved inhibitor diversity sorted into irreversible, reversible, and allosteric Mpro binders, along with a discussion of emerging resistance reports and possible evasion strategies, is aimed at stimulating continuing Mpro drug design efforts.

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Section: Inhibitors In Action-drug Performance In the Clinicmentioning

confidence: 99%

SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Fischer

Feys

2023

Future Pharmacology

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“…[176] RdRp and M PRO represent ideal antiviral targets since both proteases are critical for viral replication. [175,176] Although the efficiency and the efficacy of CNTs as an antiviral COVID-19 treatment are still unclear, [177] theoretical and computational results have been promising for the interaction of CNTs and the SARS-CoV-2 RdRP and M PRO proteases. [36,54,55,174] Molecular dynamic and molecule docking studies by Skariyachan et al [55] proved that CNTs were effective in multiple binding with targets of the SARS-CoV-2 virus, including the papain-like protease.…”

Section: Applications Of Cnts In the Treatment Of Covid-19mentioning

confidence: 99%

“…The main protease (M PRO ), also a 3C-like protease, plays a vital role in RNA virus replication and transcription. [176] RdRp and M PRO represent ideal antiviral targets since both proteases are critical for viral replication. [175,176] Although the efficiency and the efficacy of CNTs as an antiviral COVID-19 treatment are still unclear, [177] theoretical and computational results have been promising for the interaction of CNTs and the SARS-CoV-2 RdRP and M PRO proteases.…”

Section: Applications Of Cnts In the Treatment Of Covid-19mentioning

confidence: 99%

COVID‐19: Prevention, Detection, and Treatment by Using Carbon Nanotubes‐Based Materials

et al. 2023

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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was responsible for the outbreak of coronavirus disease . The respiratory illness has rapidly spread worldwide and has claimed millions of lives. Although most countries have entered the endemic phase, health authorities warned that future variants could be more virulent than the existing ones. Since clinical trials of antiviral drugs for COVID-19 may last even a year before approval, developing alternative approaches to combat the virus becomes mandatory. Previ-ously, carbon nanotubes (CNTs) have exhibited an impressive track record in controlling numerous viral diseases, including COVID-19. In this article, we review recent applications of CNTs for the prevention, detection, and treatment of COVID-19. We highlight the strategies and prospective developments of CNTs in producing personal protection equipment (PPE), vaccines, immune-triggering, development of biosensors and therapeutic strategies. Finally, the challenges, limitations, and future outlook of CNTs in combating COVID-19 are also discussed.

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“…Auch eine in-vitro-Studie (Kultivierung von Virus in Zellkulturen in Anwesenheit des Medikaments) zeigte, dass FCoV in der Lage ist, in Anwesenheit von GC376 zu mutieren und eine Resistenz gegen GC376 zu entwickeln. GC376 ist dann unwirksam gegen diese resistenten Mutanten [ 70 ] . Dies beweist, dass ein restriktiver Einsatz dieser potenten antiviralen Medikamente wichtig ist.…”

Section: Gc376unclassified

Optionen zur Therapie der felinen infektiösen Peritonitis – früher und heute

Krentz,

Bergmann,

Felten

et al. 2023

Tierarztl Prax Ausg K Kleintiere Heimtiere

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ZusammenfassungDie feline infektiöse Peritonitis (FIP) ist eine der häufigsten Infektionskrankheiten bei Katzen und verläuft unbehandelt tödlich. Bisher gibt es in Deutschland keine legal verfügbare wirksame Therapie. Therapieoptionen reichen von der symptomatischen Therapie (z. B. Glukokortikoide, Propentofyllin) über immunmodulatorische Ansätze (z. B. Interferone, Polyprenyl-Immunstimulanz) bis hin zur antiviralen Therapie mit einem Protease-Inhibitor (z. B. GC376) oder Nukleosid-Analoga (z. B. GS-441524, Remdesivir). Die symptomatische Therapie führt nicht zur Heilung der FIP, sondern nur zu einer kurzzeitigen Verbesserung der klinischen Symptome bei wenigen Katzen. Auch eine immunmodulatorische Therapie stellte sich als wenig erfolgversprechend heraus. Die antiviralen Medikamente GS-441524 und GC376 waren in mehreren Studien hochwirksam und konnten das Leben vieler an FIP erkrankten Katzen retten. Beide Wirkstoffe sind aktuell in Deutschland nicht zugelassen und können von Tierärzten nicht legal angewendet werden. Katzen dürfen aktuell nur in wenigen Ländern (z. B. Großbritannien und Australien) legal mit GS-441524 therapiert werden. GS-441524 wird daher von Katzenbesitzern in vielen anderen Ländern über den Schwarzmarkt bestellt und in Eigenregie angewendet. Dieser Artikel gibt eine Übersicht über verfügbare Therapieoptionen und einen Ausblick zur legalen Anwendung wirksamer antiviraler Medikamente.

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Adaptive Mutation in the Main Protease Cleavage Site of Feline Coronavirus Renders the Virus More Resistant to Main Protease Inhibitors

Abstract: CoVs cause serious human infections, and antiviral drugs are currently approved to treat these infections. The development of protease-targeting therapeutics for CoV infection is hindered by resistance mutations.

Cited by 10 publications

References 59 publications

SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

COVID‐19: Prevention, Detection, and Treatment by Using Carbon Nanotubes‐Based Materials

Optionen zur Therapie der felinen infektiösen Peritonitis – früher und heute

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