Targetable elements in SARS-CoV-2 S2 subunit for the design of pan-coronavirus fusion inhibitors and vaccines

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 10, 2023

Abstract The ongoing global pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome 2 (SARS‐CoV‐2), has devastating impacts on the public health and economy. Rapid viral antigenic evolution led to continual generation new variants. Of special note is recently expanding Omicron subvariants that are capable immune evasion from most existing neutralizing antibodies (nAbs). This posed challenges for prevention treatment COVID-19. Therefore, exploring broad-spectrum antiviral agents combat emerging variants imperative. In sharp contrast massive accumulation mutations within SARS-CoV-2 receptor-binding domain (RBD), S2 fusion subunit remained highly conserved among Hence, S2-based therapeutics may provide effective cross-protection against Here, we summarize developed inhibitors (e.g., nAbs, peptides, proteins, small-molecule compounds) candidate vaccines targeting elements in subunit. main focus includes all targetable elements, namely, peptide, stem helix, heptad repeats 1 (HR1-HR2) bundle. Moreover, a detailed summary characteristics action-mechanisms each class cross-reactive inhibitors, which should guide promote future design coronaviruses.

Language: Английский

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Nucleoside‐Based Drug Target with General Antimicrobial Screening and Specific Computational Studies against SARS‐CoV‐2 Main Protease

ChemistrySelect, Journal Year: 2024, Volume and Issue: 9(15)

Published: April 15, 2024

Abstract This review article aims to significantly advance the scientific community's efforts develop effective nucleoside‐based drugs for treating severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2 ) and other emerging infectious diseases. study concentrates on main viral protease (Mpro) explores compounds as potential therapeutic agents. investigation investigated impact of acylation‐induced modifications nucleoside hydroxyl group subsequent properties. Nucleoside analogs, which are recognized their diverse biochemical properties, were synthesized rigorously screened evaluate antimicrobial efficacy. In domain pharmaceutical research, computational pharmacokinetics has emerged a critical tool, especially in pursuit analogs therapeutics. silico methods aid predicting pharmacokinetic traits, interactions with crucial enzymes, stability these biological environments, thereby streamlining drug design reducing experimental costs. Concurrently, studies revealed intricate between active site protease. The amalgamation screening insights underscores emergence potent candidates inhibitory activity against SARS‐CoV‐2 M pro . Additionally, this integrates that provide valuable into SARS‐CoV‐2.

Language: Английский

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Targeting Two-Tetrad RNA G-Quadruplex in the SARS-CoV-2 RNA Genome Using Tetraphenylethene Derivatives for Antiviral Therapy

ACS Infectious Diseases, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Targeting the specific RNA conformations that are crucial for SARS-CoV-2 replication is a viable antiviral approach. The genome contains GG repeats capable of forming unstable two-tetrad G-quadruplex (GQ) structures, which exist as mix conformations, including hairpin (Hp), intra-, and intermolecular GQs. RGQ-1, originating from nucleocapsid gene's ORF, adopts dynamic equilibrium intramolecular (Hp-GQ) confirmed by CD analysis. In this study, tetraphenylethene (TPE) derivatives were developed to target Hp-GQ conformational RGQ-1. EMSA, fluorescence spectroscopy, ITC assays two TPE derivatives, TPE-MePy TPE-Allyl Py, bind thermal melting experiments indicate RGQ-1 stabilized 8.56 12.54 °C in presence respectively. Additionally, luciferase demonstrated suppressed activity 2.2-fold 3.6-fold, respectively, shifting HpGQ toward GQ conformation, suggested spectroscopy. Treatment SARS-CoV-2-infected A549 cells with reduced levels viral RNA, spikes, proteins. To explore their mechanism, preinfection postinfection treatments tested, revealing specifically postentry stages without affecting entry. These findings highlight therapeutic potential inhibiting key gene expressions critical replication.

Language: Английский

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Emerging and reemerging infectious diseases: global trends and new strategies for their prevention and control

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 11, 2024

Language: Английский

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Engineering tobacco for efficient astaxanthin production using a linker-free monocistronic dual-protein expression system and interspecific hybridization method

Plant Physiology and Biochemistry, Journal Year: 2025, Volume and Issue: 221, P. 109607 - 109607

Published: Feb. 6, 2025

Language: Английский

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The Envelope (E) Protein of SARS-CoV-2 as a Pharmacological Target

Viruses, Journal Year: 2023, Volume and Issue: 15(4), P. 1000 - 1000

Published: April 19, 2023

The COVID-19 pandemic caused by the SARS-CoV-2 virus is still a global health concern. Several spike (S) protein-based vaccines have been developed that efficiently protect human population against severe forms of COVID-19. However, some variants concern (VOCs) emerged evade protective effect vaccine-induced antibodies. Therefore, efficient and specific antiviral treatments to control are indispensable. To date, two drugs approved for mild treatment; nevertheless, more drugs, preferably broad-spectrum ready-to-use therapeutic agents new pandemics, needed. Here, I discuss PDZ-dependent protein-protein interactions viral E protein with host proteins as attractive alternatives development antivirals coronavirus.

Language: Английский

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Innate and adaptive immunity to SARS-CoV-2 and predisposing factors

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: May 9, 2023

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome (SARS-CoV-2), has affected all countries worldwide. Although some symptoms are relatively mild, others still associated with and even fatal clinical outcomes. Innate adaptive immunity important for the control of SARS-CoV-2 infections, whereas a comprehensive characterization innate immune response to COVID-19 is lacking mechanisms underlying pathogenesis host predisposing factors matter scientific debate. Here, specific functions kinetics involved in recognition resultant discussed, as well their memory vaccinations, viral-mediated evasion, current future immunotherapeutic agents. We also highlight that contribute infection, which may deepen understanding viral help identify targeted therapies attenuate infection.

Language: Английский

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Bruton's tyrosine kinase inhibition for the treatment of allergic disorders

Annals of Allergy Asthma & Immunology, Journal Year: 2024, Volume and Issue: 133(1), P. 33 - 42

Published: March 14, 2024

IgE signaling through its high-affinity receptor FcεRI is central to the pathogenesis of numerous allergic disorders. Oral inhibitors Bruton's tyrosine kinase (BTKis), which are currently FDA-approved for treatment B cell malignancies, broadly inhibit pathway in human mast cells and basophils therefore may be effective allergen-independent therapies a variety diseases. The application these drugs allergy space was previously limited by low selectivity subsequent toxicities early-generation compounds. Fortunately, next-generation, highly-selective BTKis clinical development appear have more favorable risk-benefit profiles, their likelihood being an indication increasing. Recent trials demonstrated remarkable rapid efficacy second-generation BTKi acalabrutinib preventing reactivity peanut ingestion peanut-allergic adults. Additionally, next-generation including remibrutinib effectively reduce disease activity patients with antihistamine-refractory chronic spontaneous urticaria. Finally, several under investigation early atopic dermatitis asthma. In this review, we summarize recent data supporting use as novel food allergy, anaphylaxis, urticaria, other We also discuss safety derived from utilizing both short-term dosing BTKis.

Language: Английский

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Synthesis, molecular docking analysis, molecular dynamic simulation, ADMET, DFT, and drug likeness studies: Novel Indeno[1,2-b]pyrrol-4(1H)-one as SARS-CoV-2 main protease inhibitors

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(3), P. e0299301 - e0299301

Published: March 22, 2024

Background The COVID-19 pandemic began in 2019 as a result of the advent novel coronavirus, SARS-CoV-2. At present, there are limited number approved antiviral agents for treatment COVID-19. Remdesivir, Molnupiravir, and Paxlovid have been by FDA to treat infections. Research has shown that main protease enzyme (M pro ) SARS-CoV-2 plays crucial role enzymatic processing viral polyproteins. This makes M an interesting therapeutic target combating infections caused emerging coronaviruses. Methods pharmacological effects pyrroles their derivatives wide range applications. In our study, we focused on synthesizing nine 2-arylamino-dihydro-indeno[1,2- b ] pyrrol-4(1 H )-one, with particular emphasis properties. Using silico studies involving molecular docking DFT analyses gas phase using B3LYP/6-31++G(d,p) basis set, studied these compounds respect interactions results analysis revealed synthesized exhibited favorable inhibitory effects. Notably, compound 5f demonstrated highest effectiveness against protein. Furthermore, pharmacokinetic drug-like properties 2-arylamino-dihydroindeno[1,2- )-one indicated potential promising candidates further development inhibitors targeting However, it is imperative determine vitro efficacy through comprehensive biochemical structural analyses.

Language: Английский

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Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 147, P. 107380 - 107380

Published: April 16, 2024

Language: Английский

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