Identification of a series of pyrrolo-pyrimidine based SARS-CoV-2 Mac1 inhibitors that repress coronavirus replication DOI Creative Commons
Jessica J. Pfannenstiel, Men Thi Hoai Duong, Daniel Cluff

и другие.

Опубликована: Окт. 29, 2024

ABSTRACT Coronaviruses (CoVs) can emerge from zoonotic sources and cause severe diseases in humans animals. All CoVs encode for a macrodomain (Mac1) that binds to removes ADP-ribose target proteins. SARS-CoV-2 Mac1 promotes virus replication the presence of interferon (IFN) blocks production IFN, though mechanisms by which it mediates these functions remain unknown. inhibitors could help elucidate serve as therapeutic agents against CoV-induced diseases. We previously identified compound 4a (a.k.a. MCD-628), pyrrolo-pyrimidine inhibited activity vitro at low micromolar levels. Here, we determined binding mode crystallography, further defining its interaction with Mac1. However, did not reduce CoV replication, hypothesized was due acidic side chain limiting permeability. To test this hypothesis, developed several hydrophobic derivatives . four compounds both murine hepatitis (MHV) replication: 5a , 5c 6d 6e Furthermore, only IFN γ similar deletion virus. confirm their specificity, passaged MHV identify drug-resistant mutations an alanine-to-threonine glycine-to-valine double mutation Recombinant had enhanced compared WT when treated demonstrating specificity during infection. is highly attenuated vivo indicating drug-resistance emerged expense viral fitness. IMPORTANCE present significant threats human animal health, evidenced recent outbreaks MERS-CoV SARS-CoV-2. conserved protein proteins, production, exact unclear. Inhibiting provide valuable insights into offer new avenues have unique pyrrolo-pyrimidine-based inhibitors. Notably, least two replication. Mac1, confirming mutant mice, appears come fitness cost. These results emphasize potential drug promise structure-based inhibitor design combating coronavirus infections.

Язык: Английский

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI Creative Commons
Rahul K. Suryawanshi,

Priyadarshini Jaishankar,

G.J. Correy

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 9, 2024

SARS-CoV-2 continues to pose a threat public health. Current therapeutics remain limited direct acting antivirals that lack distinct mechanisms of action and are already showing signs viral resistance. The virus encodes an ADP-ribosylhydrolase macrodomain (Mac1) plays important role in the coronaviral lifecycle by suppressing host innate immune responses. Genetic inactivation Mac1 abrogates replication

Язык: Английский

Процитировано

5
Recombinant infectious bronchitis virus containing mutations in non-structural proteins 10, 14, 15, and 16 and within the macrodomain provides complete protection against homologous challenge DOI Creative Commons
Sarah Keep, Katalin Földes, Giulia Dowgier

и другие.

Journal of Virology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 27, 2025

ABSTRACT Infectious bronchitis virus (IBV) is the etiological agent of infectious bronchitis, an acute highly contagious economically important disease chickens. Vaccination uses live attenuated vaccines (LAVs) that are generated via serial passage a virulent field isolate through embryonated hens’ eggs, typically 80–100 times. The molecular basis attenuation unknown and varies with each procedure. To investigate specifically targeted attenuation, we utilized reverse genetics to target macrodomain 1 (Mac1) domain within non-structural protein 3 M41 strain. Macrodomains found in variety viruses, including coronaviruses, have been associated modulation host’s innate response. Two recombinant IBVs (rIBVs) were specific single point mutations, either Asn42Ala (N42A) or Gly49Ser (G49S), Mac1 generating rIBVs M41K-N42A M41K-G49S, respectively. Replication vitro was unaffected, mutations stably maintained during passaging ovo . While exhibited phenotype vivo , M41K-G49S only partially attenuated. phenotypes observed do not appear be linked reduction viral replication additionally highlighted N42A mutation as method rational attenuation. chickens rIBV containing our previously identified attenuating Nsp10 14 Pro85Leu Val393Leu respectively, offered complete protection from homologous challenge. presence multiple did negatively impact vaccine efficacy. IMPORTANCE Infection Gammacoronavirus causes respiratory disease, resulting reduced weight gain reductions egg laying making it global concern for poultry industries food security. against IBV viruses (LAVs), by passages eggs. unpredictable requiring fine balance between loss virulence In this study, demonstrating can result pathogenicity. An candidate subsequently three reduce risk reversion, which completely protected targets study conserved among strains coronavirus family offering potential universally applied development.

Язык: Английский

Процитировано

0
Identification of a series of pyrrolo-pyrimidine based SARS-CoV-2 Mac1 inhibitors that repress coronavirus replication DOI Creative Commons
Jessica J. Pfannenstiel, Men Thi Hoai Duong, Daniel Cluff

и другие.

Опубликована: Окт. 29, 2024

ABSTRACT Coronaviruses (CoVs) can emerge from zoonotic sources and cause severe diseases in humans animals. All CoVs encode for a macrodomain (Mac1) that binds to removes ADP-ribose target proteins. SARS-CoV-2 Mac1 promotes virus replication the presence of interferon (IFN) blocks production IFN, though mechanisms by which it mediates these functions remain unknown. inhibitors could help elucidate serve as therapeutic agents against CoV-induced diseases. We previously identified compound 4a (a.k.a. MCD-628), pyrrolo-pyrimidine inhibited activity vitro at low micromolar levels. Here, we determined binding mode crystallography, further defining its interaction with Mac1. However, did not reduce CoV replication, hypothesized was due acidic side chain limiting permeability. To test this hypothesis, developed several hydrophobic derivatives . four compounds both murine hepatitis (MHV) replication: 5a , 5c 6d 6e Furthermore, only IFN γ similar deletion virus. confirm their specificity, passaged MHV identify drug-resistant mutations an alanine-to-threonine glycine-to-valine double mutation Recombinant had enhanced compared WT when treated demonstrating specificity during infection. is highly attenuated vivo indicating drug-resistance emerged expense viral fitness. IMPORTANCE present significant threats human animal health, evidenced recent outbreaks MERS-CoV SARS-CoV-2. conserved protein proteins, production, exact unclear. Inhibiting provide valuable insights into offer new avenues have unique pyrrolo-pyrimidine-based inhibitors. Notably, least two replication. Mac1, confirming mutant mice, appears come fitness cost. These results emphasize potential drug promise structure-based inhibitor design combating coronavirus infections.

Язык: Английский

Процитировано

0