Long COVID science, research and policy

Nature Medicine, Год журнала: 2024, Номер 30(8), С. 2148 - 2164

Опубликована: Авг. 1, 2024

Long COVID represents the constellation of post-acute and long-term health effects caused by SARS-CoV-2 infection; it is a complex, multisystem disorder that can affect nearly every organ system be severely disabling. The cumulative global incidence long around 400 million individuals, which estimated to have an annual economic impact approximately $1 trillion-equivalent about 1% economy. Several mechanistic pathways are implicated in COVID, including viral persistence, immune dysregulation, mitochondrial dysfunction, complement endothelial inflammation microbiome dysbiosis. devastating impacts on individual lives and, due its complexity prevalence, also has major ramifications for systems economies, even threatening progress toward achieving Sustainable Development Goals. Addressing challenge requires ambitious coordinated-but so far absent-global research policy response strategy. In this interdisciplinary review, we provide synthesis state scientific evidence assess human health, systems, economy metrics, forward-looking roadmap.

Язык: Английский

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Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Сен. 18, 2024

Язык: Английский

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An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

Science Translational Medicine, Год журнала: 2024, Номер 16(738)

Опубликована: Март 13, 2024

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M pro ) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing severity COVID-19, but presence resistance-conferring mutations sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized covalent hepatitis C virus inhibitor boceprevir (BPV) could serve basis for orally bioavailable inhibit SARS-CoV-2 M more efficiently than existing drugs. Performing structure-guided modifications BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with antiviral activity, pharmacokinetics, therapeutic efficacy similar or superior to those NTV. A crucial feature ML2006a4 is derivatization ketoamide reactive group improves cell permeability bioavailability. Last, was found be less sensitive several cause resistance NTV ETV occur natural population. Thus, anticipatory design can preemptively address potential mechanisms expand treatment options variants.

Язык: Английский

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Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04

Cell Discovery, Год журнала: 2024, Номер 10(1)

Опубликована: Апрель 9, 2024

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, 3C-like protease (3CLpro) that confer to novel non-covalent inhibitor, WU-04, which is currently phase III clinical trials (NCT06197217). Crystallographic analysis indicates M49K mutation destabilizes WU-04-binding pocket, impacting binding WU-04 more significantly than 3CLpro substrates. The M165V directly interferes with binding. S301P mutation, far from indirectly affects by restricting rotation 3CLpro's C-terminal tail impeding dimerization. We further explored mutations clinically used inhibitors: ensitrelvir nirmatrelvir, revealed trade-off between catalytic activity, thermostability, drug 3CLpro. found at same residue (M49) can have distinct effects on inhibitors, highlighting importance developing multiple antiviral agents different skeletons for fighting These findings enhance our understanding SARS-CoV-2 mechanisms inform therapeutics.

Язык: Английский

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Comprehensive Review of COVID-19: Epidemiology, Pathogenesis, Advancement in Diagnostic and Detection Techniques, and Post-Pandemic Treatment Strategies

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(15), С. 8155 - 8155

Опубликована: Июль 26, 2024

At present, COVID-19 remains a public health concern due to the ongoing evolution of SARS-CoV-2 and its prevalence in particular countries. This paper provides an updated overview epidemiology pathogenesis COVID-19, with focus on emergence variants phenomenon known as ‘long COVID’. Meanwhile, diagnostic detection advances will be mentioned. Though many inventions have been made combat pandemic, some outstanding ones include multiplex RT-PCR, which can used for accurate diagnosis infection. ELISA-based antigen tests also appear potential tools available future. discusses current treatments, vaccination strategies, well emerging cell-based therapies The underscores necessity us continuously update scientific understanding treatments it.

Язык: Английский

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Contributions of Hyperactive Mutations in M^pro from SARS-CoV-2 to Drug Resistance

ACS Infectious Diseases, Год журнала: 2024, Номер 10(4), С. 1174 - 1184

Опубликована: Март 12, 2024

The appearance and spread of mutations that cause drug resistance in rapidly evolving diseases, including infections by the SARS-CoV-2 virus, are major concerns for human health. Many drugs target enzymes, resistance-conferring impact inhibitor binding or enzyme activity. Nirmatrelvir, most widely used currently to treat infections, targets main protease (Mpro) preventing it from processing viral polyprotein into active subunits. Our previous work systematically analyzed Mpro reduce inhibitors; here, we investigate affect function. Hyperactive increase activity can contribute but have not been thoroughly studied. To explore how hyperactive resistance, comprehensively assessed all possible individual function using a mutational scanning approach with fluorescence resonance energy transfer (FRET)-based yeast readout. We identified hundreds significantly increased occurred both proximal distal site, consistent protein stability and/or dynamics impacting were observed 3 times more than which reduced apparent nirmatrelvir recent studies laboratory-grown viruses selected resistance. also about three prevalent sequenced isolates circulating SARS-CoV-2. findings indicate likely natural evolution provide comprehensive list future surveillance efforts.

Язык: Английский

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SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Cell chemical biology, Год журнала: 2024, Номер 31(4), С. 632 - 657

Опубликована: Апрель 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Язык: Английский

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Proof-of-concept studies with a computationally designed M ^pro inhibitor as a synergistic combination regimen alternative to Paxlovid

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(17)

Опубликована: Апрель 15, 2024

As the SARS-CoV-2 virus continues to spread and mutate, it remains important focus not only on preventing through vaccination but also treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a main protease (M pro ) DAA, has been significant for treatment patients. A limitation this however, is that antiviral component, nirmatrelvir, rapidly metabolized requires inclusion CYP450 3A4 metabolic inhibitor, ritonavir, boost levels active drug. Serious drug–drug interactions can occur Paxlovid patients who are taking other medications by CYP4503A4, particularly transplant or otherwise immunocompromised most at risk development severe symptoms. Developing an alternative improved pharmacological properties critical these By using computational structure-guided approach, we were able optimize 100 250 μM screening hit potent nanomolar inhibitor lead compound, Mpro61. In study, further evaluate Mpro61 as starting examination its mode binding M . vitro profiling established lack off-target effects, inhibition, well potential synergy currently approved alternate antiviral, molnupiravir. Development subsequent testing capsule formulation oral dosing in B6-K18-hACE2 mice demonstrated favorable properties, efficacy, molnupiravir, complete recovery from challenge SARS-CoV-2, establishing promising preclinical candidate.

Язык: Английский

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Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents

Biomolecules, Год журнала: 2024, Номер 14(7), С. 797 - 797

Опубликована: Июль 4, 2024

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it significant target for developing antiviral drugs. inhibition Mpro has emerged as promising approach therapeutic agents to treat COVID-19. This review explores structure protein and analyzes progress made understanding protein–ligand interactions inhibitors. It focuses on binding kinetics, origin, chemical these provides in-depth analysis recent clinical trials involving covalent non-covalent inhibitors emerging dual targeting Mpro. By integrating findings from literature ongoing trials, this captures current state research into inhibitors, offering comprehensive challenges directions their future development anti-coronavirus agents. information new insights inspiration medicinal chemists, paving way more effective novel COVID-19 therapies.

Язык: Английский

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Distal protein-protein interactions contribute to nirmatrelvir resistance

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Фев. 1, 2025

SARS-CoV-2 main protease, Mpro, is responsible for processing the viral polyproteins into individual proteins, including protease itself. Mpro a key target of anti-COVID-19 therapeutics such as nirmatrelvir (the active component Paxlovid). Resistance mutants identified clinically and in passage assays contain combination site mutations (e.g., E166V, E166A, L167F), which reduce inhibitor binding enzymatic activity, non-active P252L, T21I, L50F), restore fitness replication. To probe role rescue, here we use an triple mutant (L50F/E166A/L167F) that confers drug resistance with level similar to wild-type. By comparing peptide full-length protein substrates, demonstrate substrate involves more than residues site. Particularly, L50F other can enhance dimer-dimer interactions help place nsp5-6 at enzyme catalytic center. The structural activity data L50F, L50F/E166A/L167F, others underscore importance considering whole studying interactions, offers important insights function, development, design.

Язык: Английский

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