Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2

RSC Advances, Год журнала: 2023, Номер 13(50), С. 35500 - 35524

Опубликована: Янв. 1, 2023

The pandemic caused by the coronavirus SARS-CoV-2 led to a global crisis in world healthcare system. Despite some progress creation of antiviral vaccines and mass vaccination population, number patients continues grow because spread new mutations. There is an urgent need for direct-acting drugs capable suppressing or stopping main mechanisms reproduction SARS-CoV-2. Several studies have shown that successful replication virus cell requires proteolytic cleavage protein structures virus. Two proteases are crucial replicating other coronaviruses: protease (Mpro) papain-like (PLpro). In this review, we summarize essential viral proteins required its life cycle as targets chemotherapy infection provide critical summary development against COVID-19 from drug repurposing strategy up molecular design novel covalent non-covalent agents inhibiting replication. We overview choice Mpro PLpro promising pharmacological impact on cycle.

Язык: Английский

---

A SARS-CoV-2 recombinant spike protein vaccine (S-268019-b) for COVID-19 prevention during the Omicron-dominant period: A phase 3, randomised, placebo-controlled clinical trial

Vaccine, Год журнала: 2024, Номер 42(17), С. 3699 - 3709

Опубликована: Май 10, 2024

Clinical trials of new vaccines based on existing variants Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are often impacted by the emergence virus variants. We evaluated efficacy, immunogenicity, and safety S-268019-b, a recombinant spike protein subunit vaccine ancestral strain, for preventing symptomatic coronavirus disease 2019 (COVID-19) during Omicron (BA.2)-dominant period in Vietnam. In this multicentre, phase 3, randomised (2:1), observer-blind, placebo-controlled crossover study, participants received intramuscular doses (28 days apart) either 10 µg S-268019-b (Recombinant S-protein vaccine) or placebo. The primary endpoint was incidence laboratory-confirmed COVID-19 before crossover, with onset within 14 following second dose, who were seronegative reverse transcription polymerase chain reaction (RT-PCR)-negative at baseline. secondary endpoints included immunogenicity safety. total, 8,594 (S-268019-b [n = 5,727]; placebo 2,867]). Vaccine efficacy versus 39·1 % (95 confidence interval [CI]:26·6-49·5; one-sided P 0·0723). rate CI) 776·41/1,000 person-years (682·04-880·19) group 1272·87/1,000 (1101·32-1463·57) group. geometric mean titres SARS-CoV-2 neutralising antibody increased Day 57 baseline (34·66 [27·04-44·41] 2·50 (non-estimable) but not There no concerns regarding S-268019-b. did demonstrate targeted threshold against COVID-19; however, findings comparable other prophylactic ancestor strain Omicron-dominant period. demonstrated well-tolerated. ClinicalTrials.gov identifier: NCT05212948.

Язык: Английский

---

Have Diagnostics, Therapies, and Vaccines Made the Difference in the Pandemic Evolution of COVID-19 in Comparison with “Spanish Flu”?

Pathogens, Год журнала: 2023, Номер 12(7), С. 868 - 868

Опубликована: Июнь 23, 2023

In 1918 many countries, but not Spain, were fighting World War I. Spanish press could report about the diffusion and severity of a new infection without censorship for first-time, so that this pandemic is commonly defined as “Spanish flu”, even though Spain was its place origin. flu” one deadliest pandemics in history has been frequently compared with coronavirus disease (COVID)-19 pandemic. These share similarities, being both caused by highly variable transmissible respiratory RNA viruses, diversity, represented diagnostics, therapies, especially vaccines, which made rapidly available COVID-19, flu”. Most comparison studies have carried out first period when these resources either yet or their use had long started. Conversely, we wanted to analyze role advanced anti-viral agents, including monoclonal antibodies, innovative COVID-19 may containment. Early diagnosis, anti-COVID-19 vaccines markedly reduced mortality, thus preventing collapse public health services. However, influence on reduction infections re-infections, transition from endemic condition, appears be minor relevance. The high viral variability influenza probably contained development universal are easy obtained. only effective weapon still remains prevention, achieved promiscuity between animal reservoirs zoonotic diseases humans.

Язык: Английский

---

What Is the Efficacy of Sotrovimab in Reducing Disease Progression and Death in People with COVID-19 during the Omicron Era? Answers from a Real-Life Study

Viruses, Год журнала: 2023, Номер 15(8), С. 1757 - 1757

Опубликована: Авг. 17, 2023

(1) Introduction: Since May 2021, sotrovimab has been available in Italy for early treatment of SARS-CoV-2 infection and to prevent disease progression. However, some vitro studies have questioned its efficacy on Omicron variants. Therefore, we aim further investigate the real-life settings. (2) Methods: We conducted a retrospective study collecting medical records people with evaluated infectious diseases units Sassari, Foggia, Bari, Italy. included treated who did not receive any 2022. The primary outcome was evaluate reducing progression (defined as necessity starting oxygen supplementation) COVID-19-related death. secondary safety sotrovimab. (3) Results: 689 people; them, 341 were sotrovimab, while 348 treatment. Overall, registered 161 (23.4%) progressions 65 (9.4%) deaths, significant difference between not-treated (p < 0.001). In multivariate logistic regression, increasing age [OR ten years 1.23 (95%CI 1.04-1.45)] associated higher risk addition, cardiovascular 1.69 (1.01-2.80), fever 3.88 2.35-6.38)], dyspnea 7.24 4.17-12.58)] an increased contrast, vaccination 0.21 0.12-0.37)] administration 0.05 0.02-0.11)] lower developing severe COVID-19. Regarding mortality, older 1.36 1.09-1.69)] had analysis, lost statistical significance, chemotherapy haematological cancer 4.07 1.45-11.4)] those at diagnosis 3.63 2.02-6.50)] 0.37 0.20-0.68)] 0.16 0.06-0.42)] risk. Only two adverse events reported; one person complained diarrhoea few hours after administration, allergic reaction cutaneous rash itching. (4) Conclusions: Our showed that reduction death SARS-CoV-2-infected people, 70% whom over high rate, excellent safety. our results reinforce evidence about during era real-world setting.

Язык: Английский

---

Computational design of novel nanobodies targeting the receptor binding domain of variants of concern of SARS-CoV-2

PLoS ONE, Год журнала: 2023, Номер 18(10), С. e0293263 - e0293263

Опубликована: Окт. 24, 2023

The COVID-19 pandemic has created an urgent need for effective therapeutic and diagnostic strategies to manage the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, emergence of numerous variants concern (VOCs) made it challenging develop targeted therapies that are broadly specific in neutralizing virus. In this study, we aimed nanobodies (Nbs) using computational techniques can effectively neutralize receptor-binding domain (RBD) SARS-CoV-2 VOCs. We evaluated performance different protein-protein docking programs identified HDOCK as most suitable program Nb/RBD with high accuracy. Using approach, designed 14 novel Nbs binding affinity VOC RBDs. were engineered mutated amino acids interacted key RBDs, resulting higher than human angiotensin-converting enzyme (ACE2) other viral RBDs or haemagglutinins (HAs). successful development these demonstrates potential molecular modeling a low-cost time-efficient method engineering against SARS-CoV-2. have be employed RBD-neutralizing assays, facilitating identification treatment, prevention,

Язык: Английский

---

Phenothiazines Inhibit SARS-CoV-2 Entry through Targeting Spike Protein

Viruses, Год журнала: 2023, Номер 15(8), С. 1666 - 1666

Опубликована: Июль 31, 2023

Novel coronavirus disease 2019 (COVID-19), a respiratory caused by severe acute syndrome 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due the persistent emergence of new variants. Therefore, developing more effective broad-spectrum therapeutic prophylactic drugs against infection SARS-CoV-2 its variants, as well future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved identified phenothiazine derivatives with ability potently inhibit pseudotyped distinct variants concern (VOCs), including B.1.617.2 (Delta) currently circulating Omicron sublineages XBB BQ.1.1, SARS-CoV MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited pseudovirus (PsV) at early stage potentially bound spike (S) protein SARS-CoV-2, which may prevent proteolytic cleavage S protein, thereby exhibiting inhibitory activity infection. summary, our findings suggest can serve potential drug for treatment human coronaviruses (HCoVs).

Язык: Английский

---

Home Oxygen After Hospitalization for COVID-19: Results From the Multi-Center OXFORD Study

Respiratory Care, Год журнала: 2024, Номер 69(3), С. 281 - 289

Опубликована: Янв. 4, 2024

BACKGROUND:

In the first months of pandemic, prior to introduction proven-effective treatments, 15–37% patients hospitalized with COVID-19 were discharged on home oxygen. After treatments for acute established by evidence-based guidelines, little remains known about oxygen requirements following hospitalization COVID-19.

METHODS:

This was a retrospective, multi-center cohort study subjects between October 2020–September 2021 at 3 academic health centers. Information abstracted from electronic records index and 60 d after discharge. The World Health Organization Clinical Progression Scale score used identify severe

RESULTS:

Of 517 (mean age 58 y, 47% female, 42% Black, 36% Hispanic, 22% COVID-19), 81% treated systemic corticosteroids, 61% remdesivir, 2.5% tocilizumab. About one quarter (26% [95% CI 22–29]). Older (adjusted odds ratio [aOR] 1.02 per 5 y 1.02–1.02]), higher body mass (aOR kg/m² [1.00–1.04]), diabetes (yes vs no, aOR 1.73 [1.46–2.02]), (vs moderate, 3.19 [2.19–4.64]), treatment corticosteroids 30.63 [4.51–208.17]) associated an increased discharge Comorbid hypertension 0.71 [0.66–0.77) decreased Within hospital discharge, 50% had documentation pulse oximetry; in this group, discontinued 46%.

CONCLUSIONS:

41 prescribed COVID-19, even guidelines illness. Evidence-based strategies reduce requirement are needed.

Язык: Английский

---

Effective expression and characterization of the receptor binding domains in SARS-CoV-2 Spike proteins from original strain and variants of concern using Bombyx mori nucleopolyhedrovirus in silkworm

Protein Expression and Purification, Год журнала: 2024, Номер 218, С. 106450 - 106450

Опубликована: Фев. 22, 2024

Язык: Английский

---

Lancemaside A from Codonopsis lanceolata: Studies on Antiviral Activity and Mechanism of Action against SARS-CoV-2 and Its Variants of Concern

Antimicrobial Agents and Chemotherapy, Год журнала: 2022, Номер 66(12)

Опубликована: Ноя. 14, 2022

Several plant-derived natural products with anti-SARS-CoV-2 activity have been evaluated for the potential to serve as chemotherapeutic agents treatment of COVID-19. Codonopsis lanceolata (CL) has long used a medicinal herb in East Asian countries treat inflammatory diseases respiratory system but its antiviral not investigated so far. Here, we showed that CL extract and active compound lancemaside A (LA) displayed potent inhibitory against SARS-CoV-2 infection using pseudotyped entry assay system.

Язык: Английский

---

Wild-type SARS-CoV-2 neutralizing immunity decreases across variants and over time but correlates well with diagnostic testing

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Фев. 8, 2023

Importance The degree of immune protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants provided by infection versus vaccination with wild-type virus remains unresolved, which could influence future vaccine strategies. gold-standard for assessing is viral neutralization; however, few studies involve a large-scale analysis neutralization the Omicron variant sera from individuals infected virus. Objectives 1) To define to SARS-CoV-2 induced neutralizing antibodies Delta and variants. 2) determine whether clinically available data, such as infection/vaccination timing or antibody status, can predict neutralization. Methods We examined longitudinal cohort 653 subjects collected three times at 3-to-6-month intervals April 2020 June 2021. Individuals were categorized according status. Spike nucleocapsid detected via ADVIA Centaur ® (Siemens) Elecsys (Roche) assays, respectively. Healgen Scientific lateral flow assay was used detect IgG IgM spike responses. Pseudoviral assays performed on all samples using human ACE2 receptor-expressing HEK-293T cells protein pseudotyped lentiviral particles (WT), B.1.617.2 (Delta), B.1.1.529 (Omicron) Results Vaccination after led highest titers timepoints Neutralization also more durable in setting prior alone. clinical testing effectively predicted Delta. However, presence best independent predictor lower than either across groups timepoints, significant activity only present patients that first later immunized. Conclusions Participants having both had levels persistence activity. WT correlated variants, but better evidence infection. These data help explain why ‘breakthrough’ infections occurred previously vaccinated suggest observed those previous This study supports concept Omicron-specific boosters.

Язык: Английский

---