Therapeutic strategies for COVID-19: progress and lessons learned

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(6), С. 449 - 475

Опубликована: Апрель 19, 2023

Язык: Английский

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Association of Treatment With Nirmatrelvir and the Risk of Post–COVID-19 Condition

JAMA Internal Medicine, Год журнала: 2023, Номер 183(6), С. 554 - 554

Опубликована: Март 23, 2023

Importance Post–COVID-19 condition (PCC), also known as long COVID, affects many individuals. Prevention of PCC is an urgent public health priority. Objective To examine whether treatment with nirmatrelvir in the acute phase COVID-19 associated reduced risk PCC. Design, Setting, and Participants This cohort study used care databases US Department Veterans Affairs (VA) to identify patients who had a SARS-CoV-2 positive test result between January 3, 2022, December 31, were not hospitalized on day result, at least 1 factor for progression severe illness, survived first 30 days after diagnosis. Those treated oral within 5 (n = 35 717) those received no antiviral or antibody during infection (control group, n 246 076) identified. Exposures Treatment receipt based prescription records. Main Outcomes Measures Inverse probability weighted survival models estimate association (vs control) post–acute death, hospitalization, prespecified panel 13 sequelae (components PCC) reported relative scale (RR) hazard ratio (HR) absolute reduction percentage 180 (ARR). Results A total 281 793 (mean [SD] age, 61.99 [14.96]; 242 383 [86.01%] male) illness studied. Among them, 076 infection, 717 result. Compared control was (RR, 0.74; 95% CI, 0.72-0.77; ARR, 4.51%; 4.01-4.99), including 10 cardiovascular system (dysrhythmia ischemic heart disease), coagulation hematologic disorders (pulmonary embolism deep vein thrombosis), fatigue malaise, kidney disease, muscle pain, neurologic (neurocognitive impairment dysautonomia), shortness breath. Nirmatrelvir death (HR, 0.53; 0.46-0.61); 0.65%; 0.54-0.77), hospitalization 0.76; 0.73-0.80; 1.72%; 1.42-2.01). people unvaccinated, vaccinated, boosted, primary reinfection. Conclusions Relevance found that across spectrum this regardless vaccination status history prior infection; totality findings suggests may reduce adverse outcomes.

Язык: Английский

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Naturally Occurring Mutations of SARS-CoV-2 Main Protease Confer Drug Resistance to Nirmatrelvir

ACS Central Science, Год журнала: 2023, Номер 9(8), С. 1658 - 1669

Опубликована: Июль 24, 2023

The SARS-CoV-2 main protease (Mpro) is the drug target of Pfizer's oral nirmatrelvir. emergence variants with mutations in Mpro raised alarm potential resistance. To identify clinically relevant drug-resistant mutants, we systematically characterized 102 naturally occurring mutants located at 12 residues nirmatrelvir-binding site, among which 22 5 residues, including S144M/F/A/G/Y, M165T, E166 V/G/A, H172Q/F, and Q192T/S/L/A/I/P/H/V/W/C/F, showed comparable enzymatic activity to wild-type (kcat/Km < 10-fold change) while being resistant nirmatrelvir (Ki > increase). X-ray crystal structures were determined for six representative and/or without GC-376/nirmatrelvir. Using recombinant viruses generated from reverse genetics, confirmed resistance antiviral assay that reduced had attenuated viral replication. Overall, our study identified several hotspots warrant close monitoring possible clinical evidence resistance, some have already emerged independent passage assays conducted by others.

Язык: Английский

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The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir

mBio, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 10, 2023

The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with >20× increase 50% effective concentration (EC50) values nirmatrelvir (PF-07321332), PF-00835231, ensitrelvir. While two single (E166A provide low-level resistance inhibitors biochemical assay, triple mutant results highest levels (6× 72×). All are significant loss enzymatic activity, suggesting reduction fitness. Structural biology analysis indicates different reduce number inhibitor/enzyme interactions while binding substrate maintained. These observations will important interpretation development clinical setting. IMPORTANCE Paxlovid first oral antiviral approved infection. Antiviral treatments often viruses. In order guide use novel antivirals, it essential understand risk characterize changes genes proteins. this work, we describe time pathway allows develop against vitro. characteristics may predictive situation. our work management COVID-19 next-generation inhibitors.

Язык: Английский

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Transmissible SARS-CoV-2 variants with resistance to clinical protease inhibitors

Science Advances, Год журнала: 2023, Номер 9(13)

Опубликована: Март 31, 2023

Vaccines and drugs have helped reduce disease severity blunt the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, ongoing virus transmission, continuous evolution, increasing selective pressures potential to yield viral variants capable resisting these interventions. Here, we investigate susceptibility natural main protease [Mpro; 3C-like (3CLpro)] SARS-CoV-2 inhibitors. Multiple single amino acid changes in Mpro confer resistance nirmatrelvir (the active component Paxlovid). An additional clinical-stage inhibitor, ensitrelvir (Xocova), shows a different mutation profile. Importantly, phylogenetic analyses indicate that several resistant pre-existed introduction into human population are spreading. These results encourage monitoring development inhibitors other antiviral with mechanisms action profiles for combinatorial therapy.

Язык: Английский

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SARS-CoV-2 3CL ^pro mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376

Science Translational Medicine, Год журнала: 2022, Номер 15(678)

Опубликована: Окт. 4, 2022

Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is first protease inhibitor specifically developed against SARS-CoV-2 3CLpro that has been licensed for clinical use. To identify mutations confer resistance to this inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) expressed polyprotein composed of VSV glycoprotein (G), 3CLpro, and polymerase (L). Viral replication was thus dependent on autocatalytic processing precursor protein by release functional viral proteins G L, effectively inhibited nirmatrelvir. Using system, applied nirmatrelvir select mutations. Resistance confirmed retesting selected in additional VSV-based systems, an independently cellular biochemical assay, recombinant system. We demonstrate some mutants cross-resistant ensitrelvir GC376, whereas others less resistant these compounds. Furthermore, found already existed sequences have deposited NCBI GISAID databases, indicating were present circulating strains.

Язык: Английский

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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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Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir

Nature, Год журнала: 2023, Номер 622(7982), С. 376 - 382

Опубликована: Сен. 11, 2023

Язык: Английский

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Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 162, С. 114367 - 114367

Опубликована: Фев. 6, 2023

Despite the need for novel, effective therapeutics COVID-19 pandemic, no curative regimen is yet available, therefore patients are forced to rely on supportive and nonspecific therapies. Some SARS-CoV-2 proteins, like 3 C-like protease (3CLpro) or major (Mpro), have been identified as promising targets antiviral drugs. The Mpro has a role in protein processing well pathogenesis of virus, could be useful therapeutic target. drug nirmatrelvir can keep from replicating through inhibiting Mpro. Nirmatrelvir was combined with another HIV inhibitor, ritonavir, create Paxlovid (Nirmatrelvir/Ritonavir). metabolizing enzyme cytochrome P450 A inhibited by ritonavir lengthen half-life nirmatrelvir, so rintonavir acts pharmacological enhancer. exhibits potent activity against current coronavirus variants, despite significant alterations viral genome. Nevertheless, there still several unanswered questions. This review summarizes literature efficacy treating infection, also their safety possible side effects.

Язык: Английский

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Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(3), С. 103004 - 103004

Опубликована: Фев. 10, 2023

SARS-CoV-2 is the causative agent of COVID-19. The main viral protease (Mpro) an attractive target for antivirals. clinically approved drug nirmatrelvir and clinical candidate ensitrelvir have so far showed great potential treatment infection. However, broad use antivirals often associated with resistance generation. Herein, we enzymatically characterized 14 naturally occurring Mpro polymorphisms that are close to binding site these Nirmatrelvir retained its potency against most tested, while mutants G143S Q189K were diminished inhibition constants. For ensitrelvir, constants observed M49I, G143S, R188S, but not Q189K, suggesting a distinct profile between inhibitors. In addition, crystal structures selected revealed interactions critical loss potency. conclusion, our data will assist monitoring resistant strains, support design combined therapy, as well development next generation

Язык: Английский

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