Dual‐Locking the SARS‐CoV‐2 Spike Trimer: An Amphipathic Molecular “Bolt” Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition DOI Creative Commons
Shiliang Li, Fang Ye, Yucheng Zheng

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 26, 2025

Abstract The SARS‐CoV‐2 spike (S) protein, a trimeric structure comprising three receptor binding domains (RBDs) and N‐terminal (NTDs), undergoes substantial conformational changes to fusion‐prone open state for angiotensin‐converting enzyme 2 (ACE2) host cell infection. Stabilizing its closed is key antiviral strategy but remains challenging. Here, we introduce S416, novel amphipathic molecule acting as “molecular bolt”. Cryo‐EM study reveals that S416 binds concurrently six sites across two distinct druggable interfaces: molecules at the RBD‐RBD interfaces NTD‐RBD interfaces. This unique “dual‐locking” mechanism, driven by S416's polar carboxyl head nonpolar phenylthiazole tail, robustly stabilizes trimer in locked, conformation through strong inter‐domain interactions, reducing structural flexibility atomic fluctuations compared apo resolved synchronously. Crucially, these are conserved human‐infecting coronaviruses, suggesting potential broad‐spectrum targets. Our findings demonstrate highly dynamic can be effectively stabilized an molecular bolt targeting both inter‐ intra‐monomer interfaces, offering promising against emerging coronaviruses.

Language: Английский

Procyanidins inhibit alphacoronavirus infection by reducing interferon antagonism DOI
Yi Liu, Xue Wang, Xuefei Wang

et al.

Phytomedicine, Journal Year: 2025, Volume and Issue: 140, P. 156549 - 156549

Published: Feb. 25, 2025

Language: Английский

Citations

0
T and B cell responses in different immunization scenarios for COVID-19: a narrative review DOI Creative Commons
Eva Piano Mortari, Pier Francesco Ferrucci,

Irini Zografaki

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 18, 2025

Vaccines against COVID-19 have high efficacy and low rates of adverse events. However, none the available vaccines provide sterilizing immunity, reinfections remain possible. This review aims to summarize immunological responses elicited by different immunization strategies, examining roles homologous heterologous vaccination hybrid immunity. Homologous regimens exhibit considerable variation in immune depending on vaccine platform, particularly concerning antibody titers, B cell activation, T responses. mRNA vaccines, such as mRNA-1273 BNT162b2, consistently generate higher more durable levels neutralizing antibodies memory cells compared adenovirus-based like Ad26.COV2.S ChAdOx1. The combination two distinct platforms, each targeting pathways, seems be effective promoting long-lasting potent heterogeneity studies, dosing schemes, succession new variants, subjects' background do not allow for a definitive conclusion. Overall, combining sequentially viral vector may deliver balanced robust humoral cellular response regimens. Hybrid which arises from SARS-CoV-2 infection preceded or followed produces markedly stronger than either alone. variants concern varies both platform prior status. immunity leads broader repertoire, providing enhanced neutralization concern. Heterologous further opportunities enhance responses, offering protection greater durability all-cause mortality, symptomatic severe COVID, serious events at present it is possible infer effects between schemes. Next-generation could involve tweaks these designs changes delivery mechanisms that might improve performance.

Language: Английский

Citations

0
An Intranasal Nanomedicine Functions as Both Potent Broad‐spectrum Viral Inhibitor and Quasi‐Vaccine DOI

Jingran Chen,

Ying Li,

Li Xiao

et al.

Advanced Functional Materials, Journal Year: 2025, Volume and Issue: unknown

Published: April 2, 2025

Abstract Antivirals that exert rapid inhibition and vaccines provide long‐term prevention are both of paramount importance for the intervening against fatal viral infections. Clearly, it will be highly desirable to integrate two strategies into a single antiviral agent; however, such concept is challenging achieve has not been explored yet. Herein, an unprecedented broad‐spectrum photothermal nanomedicine reported with unique advantages offer protection vaccine‐like prevention. This rationally engineered gold nanorod capable targeting glycan‐shield various viruses exerting multiple unparalleled mechanisms, i.e., blocking virus‐cell attachment, inducing aggregation, enhancing macrophage phagocytosis, promoting virions lysis, initiating immune response. As such, exhibits potent efficacy toward variety viruses, including severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) its major variants, lassa virus (LASV) porcine deltacoronavirus (PDCoV), EC 50 value as low tens pM level nearly 100% rate. Significantly, in vivo intranasal administration authentic PDCoV challenge demonstrates killing, effective inflammation suppression production protective IgA IgG. Thus, proof‐of‐concept, this study provides new insights evidences design “two‐way player” agents can simultaneously treat prevent

Language: Английский

Citations

0
Identification of potential SARS-CoV-2 inhibitors among well-tolerated drugs using drug repurposing and in vitro approaches DOI Creative Commons

Betül Oruçoğlu,

İdi̇l Çeti̇n, Cem Şimşek

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: April 22, 2025

The 3C-like protease (3CLpro) is essential in the SARS-CoV-2 life cycle and a promising target for antiviral drug discovery, as no similar proteases exist humans. This study aimed to identify effective inhibitors among FDA-approved drugs. Previous computational analysis revealed several drugs with high binding affinity 3CLpro active site. In vitro enzymatic assays confirmed that ten of these effectively inhibited enzyme. To evaluate their impact on viral replication, we used non-infectious sub-genomic replicons lung intestinal cells. Amcinonide, eltrombopag, lumacaftor, candesartan, nelfinavir replication at low micromolar concentrations. Lumacaftor showed IC50 values 964 nM Caco-2 cells 458 Calu-3 cells, while candesartan had 714 1.05 µM, respectively. Furthermore, dual combination experiments amcinonide, pimozide, eltrombopag acted potent nanomolar concentrations when combined candesartan. highlights emphasizes potential repurposing treatments. These findings support future clinical trials may lead breakthroughs COVID-19 treatment strategies.

Language: Английский

Citations

0
Dual‐Locking the SARS‐CoV‐2 Spike Trimer: An Amphipathic Molecular “Bolt” Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition DOI Creative Commons
Shiliang Li, Fang Ye, Yucheng Zheng

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 26, 2025

Abstract The SARS‐CoV‐2 spike (S) protein, a trimeric structure comprising three receptor binding domains (RBDs) and N‐terminal (NTDs), undergoes substantial conformational changes to fusion‐prone open state for angiotensin‐converting enzyme 2 (ACE2) host cell infection. Stabilizing its closed is key antiviral strategy but remains challenging. Here, we introduce S416, novel amphipathic molecule acting as “molecular bolt”. Cryo‐EM study reveals that S416 binds concurrently six sites across two distinct druggable interfaces: molecules at the RBD‐RBD interfaces NTD‐RBD interfaces. This unique “dual‐locking” mechanism, driven by S416's polar carboxyl head nonpolar phenylthiazole tail, robustly stabilizes trimer in locked, conformation through strong inter‐domain interactions, reducing structural flexibility atomic fluctuations compared apo resolved synchronously. Crucially, these are conserved human‐infecting coronaviruses, suggesting potential broad‐spectrum targets. Our findings demonstrate highly dynamic can be effectively stabilized an molecular bolt targeting both inter‐ intra‐monomer interfaces, offering promising against emerging coronaviruses.

Language: Английский

Citations

0