Research Square (Research Square), Год журнала: 2024, Номер unknown
Опубликована: Ноя. 21, 2024
Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that human infections suggests risk future coronavirus outbreak by spillover infection from animal reservoirs remains high
Язык: Английский
Nature Reviews Microbiology, Год журнала: 2024, Номер 22(7), С. 391 - 407
Опубликована: Апрель 15, 2024
Язык: Английский
Процитировано
20
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Окт. 9, 2024
SARS-CoV-2 JN.1 with an additional L455S mutation on spike when compared its parental variant BA.2.86 has outcompeted all earlier variants to become the dominant circulating variant. Recent studies investigated immune resistance of but factors are speculated contribute global dominance, which remain elusive until today. Here, we find that a higher infectivity than in differentiated primary human nasal epithelial cells (hNECs). Mechanistically, demonstrate gained over associates increased entry efficiency conferred by and better cleavage hNECs. Structurally, S455 altered mode binding protein ACE2 at
Язык: Английский
Процитировано
13
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июнь 7, 2024
Abstract Monoclonal antibody (mAb) therapeutics hold promise for both preventing and treating infectious diseases, especially among vulnerable populations. However, the emergence of various variants severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges current mAb treatments, emphasizing need more potent broadly neutralizing antibodies. In this study, we employed an unbiased screening approach to discover antibodies successfully isolated two mAbs from individuals with only exposure ancestral SARS-CoV-2. One these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum SARS-CoV-2 variants, including latest JN.1 KP.2 consistent IC 50 values ranging ∼1 5 ng/mL. Notably, it also displayed broad neutralization activity SARS-CoV related sarbecoviruses, such as WIV1, SHC014, RaTG13, GD-Pangolin. Structural analysis revealed that target shared hotspot but mutation-resistant epitopes, their Fabs locking RBD in “down” conformation through interactions adjacent RBDs, cross-linking Spike trimers into di-trimers block viral infection. vivo studies conducted JN.1-infected hamster model validated protective efficacy its therapeutic potential. These findings suggest that, meticulous approaches, rare activities sarbecoviruses can be identified exclusively virus exposure.
Язык: Английский
Процитировано
5
Communications Biology, Год журнала: 2025, Номер 8(1)
Опубликована: Март 6, 2025
The emergence of various SARS-CoV-2 variants presents challenges for antibody therapeutics, emphasizing the need more potent and broadly neutralizing antibodies. Here, we employed an unbiased screening approach successfully isolated two antibodies from individuals with only exposure to ancestral SARS-CoV-2. One these antibodies, CYFN1006-1, exhibited robust cross-neutralization against a spectrum variants, including latest KP.2, KP.3 XEC, consistent IC50 values ranging ~1 5 ng/mL. It also displayed broad neutralization activity SARS-CoV related sarbecoviruses. Structural analysis revealed that target shared hotspot but mutation-resistant epitopes, their Fabs locking receptor binding domains (RBDs) in "down" conformation through interactions adjacent RBDs, cross-linking Spike trimers into di-trimers. In vivo studies conducted JN.1-infected hamster model validated protective efficacy CYFN1006-1. These findings suggest activities can be identified exclusively virus exposure.
Язык: Английский
Процитировано
0
Journal of Medical Virology, Год журнала: 2024, Номер 96(2)
Опубликована: Фев. 1, 2024
Abstract Interferons (IFNs) are critical for immune defense against pathogens. While type‐I and ‐III IFNs have been reported to inhibit SARS‐CoV‐2 replication, the antiviral effect mechanism of type‐II IFN remain largely unknown. Here, we evaluate activity (IFNγ) using human lung epithelial cells (Calu3) ex vivo tissues. In this study, found that IFNγ suppresses replication in both Calu3 Moreover, treatment does not significantly modulate expression entry‐related factors induces a similar level pro‐inflammatory response tissues when compared with IFNβ treatment. Mechanistically, show overexpression indoleamine 2,3‐dioxygenase 1 (IDO1), which is most profoundly induced by IFNγ, substantially restricts ancestral Alpha Delta variants. Meanwhile, loss‐of‐function study reveals IDO1 knockdown restores restricted cells. We further l ‐tryptophan, substrate IDO1, partially rescues IFNγ‐mediated inhibitory on Collectively, these results suggest potently inhibits through IDO1‐mediated response.
Язык: Английский
Процитировано
2
Cell & Bioscience, Год журнала: 2024, Номер 14(1)
Опубликована: Сен. 6, 2024
Язык: Английский
Процитировано
1
Опубликована: Янв. 1, 2024
Язык: Английский
Процитировано
0
Al-Mustaqbal Journal of Pharmaceutical and Medical Sciences, Год журнала: 2024, Номер 2(1)
Опубликована: Май 30, 2024
The worldwide outbreak of the COVID-19 pandemic compelled scientists to develop new, highly effective therapeutic approaches fight it. Multitarget drugs have been proven be in managing complex disorders. But designing multitarget is a great challenge. In this study, prevent lack efficacy due viral mutation escape, multi-target agent against virus was discovered. As crucial targets, RNA-dependent RNA polymerase (RdRp), main protease (Mpro), and SARS-CoV-2 Nsp15 were selected. A pharmacophore model developed using native ligands chosen targets. This used screen ZINC Drug Database for commercially available compounds having similar features experimentally tested drugs. Pharmacophore-based virtual screening yielded 1331 hits, which further docked into binding sites selected proteins PyRx AutoDock Vina. Evaluation docking results revealed that glisoxepide (Zn 00537804) has highest scores three target proteins. It showed free energies -6.8, -6.2, -7.8 kcal/mol towards Mpro, Nsp15, RdRp, respectively. According an silico ADME follows Lipinski's rule. molecular dynamics simulation study subsequent investigations had good stability within active promise as potential treatment still needs evaluated through experimental research.
Язык: Английский
Процитировано
0
Journal of Medical Virology, Год журнала: 2024, Номер 96(11)
Опубликована: Ноя. 1, 2024
ABSTRACT Elucidating the detailed features of emerging SARS‐CoV‐2 strains both in vitro and vivo is indispensable for development effective vaccines or drugs against viral infection. We thoroughly characterized virological pathogenic eight different pandemic strains, from WT strain to current circulating sublineage EG.5.1, vivo. Besides observed Vero E6 cells, Omicron variants, BA.1 exhibited enhanced infectious effects upper respiratory tract K18 human angiotensin‐converting enzyme (ACE2) (K18 hACE2) transgenic mice. Both XBB.1.9.1 EG.5.1 presented stronger tropism brain, which could be main reason increased lethal on In addition, pathogenesis comparisons among all these viruses C57BL/6JGpt mice indicated that variant two new sublineages possessed dual tropisms mice, were further confirmed by subsequent bioinformatic analyses actual affinity comparison between RBDs mouse receptor ACE2. Furthermore, immunocompromised BKS‐db found more susceptible compared revealed infectivity was determined its host immunocompetence. Thus, this study not only contributes a systematic understanding but also provides insights combat potential future surges variants.
Язык: Английский
Процитировано
0
Research Square (Research Square), Год журнала: 2024, Номер unknown
Опубликована: Ноя. 21, 2024
Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that human infections suggests risk future coronavirus outbreak by spillover infection from animal reservoirs remains high
Язык: Английский
Процитировано
0