A new generation Mpro inhibitor with potent activity against SARS-CoV-2 Omicron variants

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Март 16, 2023

Abstract Emerging SARS-CoV-2 variants, particularly the Omicron variant and its sublineages, continually threaten global public health. Small molecule antivirals are an effective treatment strategy to fight against virus. However, first-generation either show limited clinical efficacy and/or have some defects in pharmacokinetic (PK) properties. Moreover, with increased use of these drugs across globe, they face great pressure drug resistance. We herein present discovery characterization a new generation antiviral candidate (SY110), which is potent selective inhibitor main protease (M pro ). This compound displayed vitro activity not only predominant sublineage BA.5, but also other highly pathogenic human coronaviruses including SARS-CoV-1 MERS-CoV. In Omicron-infected K18-hACE2 mouse model, oral SY110 significantly lowered viral burdens lung alleviated virus-induced pathology. Importantly, possesses favorable PK properties high exposure bioavailability, outstanding safety profile. Furthermore, exhibited sensitivity several drug-resistance M mutations. Collectively, this investigation provides promising variants SARS-CoV-2.

Язык: Английский

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Emergence and antibody evasion of BQ, BA.2.75 and SARS-CoV-2 recombinant sub-lineages in the face of maturing antibody breadth at the population level

EBioMedicine, Год журнала: 2023, Номер 90, С. 104545 - 104545

Опубликована: Март 30, 2023

Язык: Английский

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The viral fitness and intrinsic pathogenicity of dominant SARS-CoV-2 Omicron sublineages BA.1, BA.2, and BA.5

EBioMedicine, Год журнала: 2023, Номер 95, С. 104753 - 104753

Опубликована: Авг. 12, 2023

Among the Omicron sublineages that have emerged, BA.1, BA.2, BA.5, and their related resulted in largest number of infections. While recent studies demonstrated all robustly escape neutralizing antibody response, it remains unclear on whether these share any pattern evolutionary trajectory replication efficiency intrinsic pathogenicity along respiratory tract.We compared virological features, capacity dominant BA.2 BA.5 human nasal epithelium, characterized K18-hACE2, A129, young C57BL/6, aged C57BL/6 mice.We found replicated most robustly, followed by differentiated epithelium. Consistently, infection higher viral gene copies, infectious titres more abundant antigen expression turbinates infected K18-hACE2 transgenic mice. In contrast, are continuously attenuated lungs mice, leading to decreased pathogenicity. Nevertheless, lung manifestations remain severe sublineages-infected A129 mice.Our results suggested might be gaining fitness upper tract, therefore highlighting importance global surveillance emergence hyper-transmissive sublineages. On contrary, is further lower tract. Effective vaccination other precautions should place prevent infections immunocompromised populations at risk.A full list funding bodies contributed this study can Acknowledgements section.

Язык: Английский

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Evolution of the SARS-CoV-2 Omicron spike

Cell Reports, Год журнала: 2023, Номер 42(12), С. 113444 - 113444

Опубликована: Ноя. 18, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern, first identified in November 2021, rapidly spread worldwide and diversified into several subvariants. spike (S) protein accumulated an unprecedented number sequence changes relative to previous variants. In this review, we discuss how S structural features modulate host cell receptor binding, virus entry, immune evasion highlight these differentiate from We also examine key properties track across the still-evolving subvariants importance continuing surveillance evolution over time.

Язык: Английский

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Altered host protease determinants for SARS-CoV-2 Omicron

Science Advances, Год журнала: 2023, Номер 9(3)

Опубликована: Янв. 20, 2023

Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While role host transmembrane protease serine in SARS-CoV-2 is widely recognized, involvement other proteases capable facilitating entry remains incompletely explored. Here, we show that multiple members from membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin families can mediate entry. Inhibition MT-MMPs significantly reduces replication vitro vivo. Mechanistically, cleave angiotensin-converting enzyme facilitate spike-mediated fusion. We further demonstrate Omicron BA.1 has an increased efficiency on MT-MMP usage, while altered usage for virus compared with ancestral SARS-CoV-2. These results reveal additional determinants enhance our understanding biology

Язык: Английский

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Molecular Evolution of SARS-CoV-2 during the COVID-19 Pandemic

Genes, Год журнала: 2023, Номер 14(2), С. 407 - 407

Опубликована: Фев. 4, 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced diverse molecular variants during its recent expansion in humans that caused different transmissibility and severity of the associated disease as well resistance to monoclonal antibodies polyclonal sera, among other treatments. In order understand causes consequences observed SARS-CoV-2 diversity, a variety studies investigated evolution this virus humans. general, evolves with moderate rate evolution, 10

Язык: Английский

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Determinants and Mechanisms of the Low Fusogenicity and High Dependence on Endosomal Entry of Omicron Subvariants

mBio, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 10, 2023

Omicron has been shown to predominantly use the endosomal entry pathway, resulting in reduced lung tropism and disease severity; however, underlying mechanism is not fully understood. In addition, whether most recent subvariants, including BA.5 BA.2.75, same pathway as their ancestor for currently known.

Язык: Английский

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Antigenic evolution of SARS coronavirus 2

Current Opinion in Virology, Год журнала: 2023, Номер 62, С. 101349 - 101349

Опубликована: Авг. 28, 2023

SARS coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, emerged in China December 2019. Vaccines developed were very effective initially, however, virus has shown remarkable evolution with multiple variants spreading globally over last three years. Nowadays, newly emerging Omicron lineages are gaining substitutions at a fast rate, resulting escape from neutralization by antibodies that target Spike protein. Tools to map impact on further antigenic SARS-CoV-2, such as cartography, may be helpful update SARS-CoV-2 vaccines. In this review, we focus highlighting protein individually and combination immune escape.

Язык: Английский

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SARS-CoV-2 Omicron subvariants exhibit distinct fusogenicity, but similar sensitivity, to pan-CoV fusion inhibitors

Emerging Microbes & Infections, Год журнала: 2023, Номер 12(1)

Опубликована: Фев. 7, 2023

Continuous emergence of the Omicron variant, along with its subvariants, has caused an increasing number infections, reinfections, and vaccine-breakthrough seriously threatening human health. Recently, several new such as BA.5, BA.2.75, BA.4.6, BF.7, bearing distinct mutation profiles in their spike (S) proteins, have significantly increased capacity to evade vaccine-induced immunity shown enhanced infectivity transmissibility, quickly becoming dominant sublineages. In this study, we found S proteins these subvariants 2- 4-fold more efficient membrane fusion kinetics than that original variant (BA.1), indicating novel might possess pathogenicity. We also identified peptide-based pan-CoV inhibitors, EK1 EK1C4, showed equal efficacy against mediated by noted infection pseudoviruses. Additionally, either immune sera induced wild-type (WT) SARS-CoV-2 RBD-based vaccine or BA.2 convalescent potent synergism both WT various further suggesting EK1-based inhibitors are promising candidates for development clinical antiviral agents currently circulating subvariants.

Язык: Английский

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Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3

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

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