Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry DOI Creative Commons
Haofeng Wang, Qi Yang,

Xiaoce Liu

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Ноя. 21, 2023

Abstract Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants concern. Host proteases, TMPRSS2 CTSL/CTSB cleave spike play a crucial role in two alternative pathways viral entry are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition these proteases determine their complex structures with respective Furthermore, applying inhibitors simultaneously block both synergistic antiviral effect. Notably, devise bispecific compound, 212-148 , exhibiting dual-inhibition ability CTSL/CTSB, demonstrate activity various profiles. Our findings offer an approach for discovery antivirals, well application treatment pathogenic infections similar pathways.

Язык: Английский

Therapeutic strategies for COVID-19: progress and lessons learned DOI Open Access
Guangdi Li, Rolf Hilgenfeld, Richard J. Whitley

и другие.

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

Опубликована: Апрель 19, 2023

Язык: Английский

Процитировано

405
SARS-CoV-2 viral load and shedding kinetics DOI Open Access
Olha Puhach, Benjamin Meyer, Isabella Eckerle

и другие.

Nature Reviews Microbiology, Год журнала: 2022, Номер unknown

Опубликована: Дек. 2, 2022

Язык: Английский

Процитировано

313
The SARS-CoV-2 nucleocapsid protein: its role in the viral life cycle, structure and functions, and use as a potential target in the development of vaccines and diagnostics DOI Creative Commons
Wenbing Wu, Ying Cheng, Hong Zhou

и другие.

Virology Journal, Год журнала: 2023, Номер 20(1)

Опубликована: Янв. 10, 2023

Coronavirus disease 2019 (COVID-19) continues to take a heavy toll on personal health, healthcare systems, and economies around the globe. Scientists are expending tremendous effort develop diagnostic technologies for detecting positive infections within shortest possible time, vaccines drugs specifically prevention treatment of COVID-19 disease. At same emerging novel variants have raised serious concerns about vaccine efficacy. The SARS-CoV-2 nucleocapsid (N) protein plays an important role in coronavirus life cycle, participates various vital activities after virus invasion. It has attracted large amount attention drug development. Here, we summarize latest research N protein, including its structure function, post-translational modifications addition involvement liquid-liquid phase separation (LLPS) use as basis development techniques.

Язык: Английский

Процитировано

140
TMEM106B is a receptor mediating ACE2-independent SARS-CoV-2 cell entry DOI Creative Commons
Jim Baggen, Maarten Jacquemyn, Leentje Persoons

и другие.

Cell, Год журнала: 2023, Номер 186(16), С. 3427 - 3442.e22

Опубликована: Июль 7, 2023

SARS-CoV-2 is associated with broad tissue tropism, a characteristic often determined by the availability of entry receptors on host cells. Here, we show that TMEM106B, lysosomal transmembrane protein, can serve as an alternative receptor for into angiotensin-converting enzyme 2 (ACE2)-negative Spike substitution E484D increased TMEM106B binding, thereby enhancing TMEM106B-mediated entry. TMEM106B-specific monoclonal antibodies blocked infection, demonstrating role in viral Using X-ray crystallography, cryogenic electron microscopy (cryo-EM), and hydrogen-deuterium exchange mass spectrometry (HDX-MS), luminal domain (LD) engages receptor-binding motif spike. Finally, promotes spike-mediated syncytium formation, suggesting fusion. Together, our findings identify ACE2-independent infection mechanism involves cooperative interactions heparan sulfate TMEM106B.

Язык: Английский

Процитировано

101
COVID-19 and the Vasculature: Current Aspects and Long-Term Consequences DOI Creative Commons
Berenice Martínez-Salazar, Melle Holwerda, Chiara Stüdle

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2022, Номер 10

Опубликована: Фев. 15, 2022

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was first identified in December 2019 as a novel respiratory pathogen and is the causative agent of Corona Virus disease (COVID-19). Early on during this pandemic, it became apparent that SARS-CoV-2 not only restricted to infecting tract, but virus also found other tissues, including vasculature. Individuals with underlying pre-existing co-morbidities like diabetes hypertension have been more prone develop severe illness fatal outcomes COVID-19. In addition, critical clinical observations made COVID-19 patients include hypercoagulation, cardiomyopathy, heart arrythmia, endothelial dysfunction, which are indicative for an involvement vasculature pathology. Hence, review summarizes impact infection details how promotes (chronic) vascular inflammation. We provide general overview SARS-CoV-2, its entry determinant Angiotensin-Converting Enzyme II (ACE2) detection extrapulmonary tissue. Further, we describe relation between cardiovascular diseases (CVD) their Clinical findings changes reviewed detail recent evidence from vitro studies susceptibility cells discussed. conclude current notions contribution events long term consequences COVID-19, known “Long-COVID-syndrome”. Altogether, our provides detailed perspectives influence

Язык: Английский

Процитировано

87
Novel cleavage sites identified in SARS-CoV-2 spike protein reveal mechanism for cathepsin L-facilitated viral infection and treatment strategies DOI Creative Commons
Miao-Miao Zhao, Yun Zhu, Li Zhang

и другие.

Cell Discovery, Год журнала: 2022, Номер 8(1)

Опубликована: Июнь 6, 2022

The spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an important target for vaccine and drug development. However, the rapid emergence variant strains with mutated S proteins has rendered many treatments ineffective. Cleavage by host proteases essential viral infection. Here, we discovered that contains two previously unidentified Cathepsin L (CTSL) cleavage sites (CS-1 CS-2). Both are highly conserved among all known SARS-CoV-2 variants. Our structural studies revealed CTSL promoted to adopt receptor-binding domain (RBD) "up" activated conformations, facilitating membrane fusion. We confirmed during infection emerged variants (including recently Omicron variant) pseudovirus (PsV) experiment. Furthermore, found CTSL-specific inhibitors not only blocked PsV/live virus in cells but also reduced live ex vivo lung tissues both human donors ACE2-transgenic mice. Finally, showed exhibited excellent In effects prevent work demonstrated inhibition a promising approach development future mutation-resistant therapy.

Язык: Английский

Процитировано

80
SARS-CoV-2 biology and host interactions DOI
Silvio Steiner, Annika Kratzel, G. Tuba Barut

и другие.

Nature Reviews Microbiology, Год журнала: 2024, Номер 22(4), С. 206 - 225

Опубликована: Янв. 15, 2024

Язык: Английский

Процитировано

78
ACE2-dependent and -independent SARS-CoV-2 entries dictate viral replication and inflammatory response during infection DOI
Tianhao Duan, Changsheng Xing, Junjun Chu

и другие.

Nature Cell Biology, Год журнала: 2024, Номер 26(4), С. 628 - 644

Опубликована: Март 21, 2024

Язык: Английский

Процитировано

21
Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung DOI Creative Commons
Ting-Hsuan Wu, Kyle J. Travaglini, Arjun Rustagi

и другие.

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(6)

Опубликована: Апрель 10, 2024

Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects SARS-CoV-2 virus by productively infecting healthy human lung tissue using scRNA-seq reconstruct the transcriptional program “infection pseudotime” for individual cell types. predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands viral RNA molecules, taking over 60% transcriptome forming dense bodies while inducing host profibrotic (TGFB1, SPP1) inflammatory (early interferon response, CCL2/7/8/13, CXCL10, IL6/10) programs destroying architecture. Infected alveolar (AMs) showed none these extreme responses. Spike-dependent entry into AMs used ACE2 Sialoadhesin/CD169, whereas IM DC-SIGN/CD209. These results identify IMs as a prominent site takeover, focus inflammation fibrosis, suggest targeting CD209 prevent early pathology pneumonia. This approach be generalized any infection evaluate therapeutics.

Язык: Английский

Процитировано

17
Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry DOI Creative Commons
Selvin Noé Palacios-Rápalo, Luis Adrián De Jesús‐González, Carlos Daniel Cordero‐Rivera

и другие.

Frontiers in Immunology, Год журнала: 2021, Номер 12

Опубликована: Дек. 16, 2021

Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), causal agent of Disease 2019 (COVID-19), represents a global problem for human health that involves host lipid homeostasis. Regarding, rafts are functional membrane microdomains with highly and tightly packed molecules. These regions enriched in sphingolipids cholesterol recruit concentrate several receptors molecules involved pathogen recognition cellular signaling. Cholesterol-rich have multiple functions viral replication; however, their role SARS-CoV-2 infection remains unclear. In this review, we discussed novel evidence on cholesterol-rich as platform entry, where such angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), Toll-like (TLRs), transmembrane serine proteases (TMPRSS), CD-147 HDL-scavenger receptor B type 1 (SR-B1) recruited interaction spike protein. FDA-approved drugs statins, metformin, hydroxychloroquine, cyclodextrins (methyl-β-cyclodextrin) can disrupt to regulate key immune signaling pathways triggered by infection. Taken together, better knowledge SARS-CoV-2-host interactions will provide valuable insights into pathogenesis identification therapeutic targets.

Язык: Английский

Процитировано

89