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

et al.

Published: Oct. 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.

Language: Английский

Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target DOI
Sarah Wazir, Tomi A. O. Parviainen, Jessica J. Pfannenstiel

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(8), P. 6519 - 6536

Published: April 9, 2024

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied compound binding mode using X-ray crystallography, allowing us to design analogues. Compound 27 (MDOLL-0229) an IC50 2.1 μM and was selective CoV Mac1 proteins after profiling activity against a panel viral human proteins. improved potency allowed testing its effect on replication, indeed, inhibited replication both murine hepatitis (MHV) prototypes SARS-CoV-2. Sequencing drug-resistant MHV identified mutations in demonstrating specificity 27. is first Mac1-targeted small molecule demonstrated inhibit cell model.

Language: Английский

Citations

9
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI Creative Commons
Rahul K. Suryawanshi,

Priyadarshini Jaishankar,

G.J. Correy

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 9, 2024

Abstract 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 vivo potentiating However, it is unknown whether this can be achieved pharmacologic inhibition therefore exploited therapeutically. Here we report potent selective lead small molecule, AVI-4206, effective model infection. Cellular models indicate AVI-4206 has high target engagement weakly inhibit gamma interferon- catalytic activity-dependent manner; stronger antiviral effect for observed human airway organoids. In animal severe infection, reduces replication, potentiates responses, leads survival benefit. Our results provide pharmacological proof concept valid therapeutic via novel immune-restoring mechanism could potentially synergize with existing therapies targeting distinct, essential aspects life cycle. This approach more widely used other macrodomains develop beyond COVID-19.

Language: Английский

Citations

5
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI Open Access
Rahul K. Suryawanshi,

Priyadarshini Jaishankar,

G.J. Correy

et al.

Published: Jan. 6, 2025

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 vivo potentiating However, it is unknown whether this can be achieved pharmacologic inhibition therefore exploited therapeutically. Here we report potent selective lead small molecule, AVI-4206, effective model infection. Cellular models indicate AVI-4206 has high target engagement weakly inhibit gamma interferon- catalytic activity-dependent manner; stronger antiviral effect for observed human airway organoids. In animal severe infection, reduces replication, potentiates responses, leads survival benefit. Our results provide pharmacological proof concept valid therapeutic via novel immune-restoring mechanism could potentially synergize with existing therapies targeting distinct, essential aspects life cycle. This approach more widely used other macrodomains develop beyond COVID-19.

Language: Английский

Citations

0
The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI Open Access
Rahul K. Suryawanshi,

Priyadarshini Jaishankar,

G.J. Correy

et al.

Published: Jan. 6, 2025

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 vivo potentiating However, it is unknown whether this can be achieved pharmacologic inhibition therefore exploited therapeutically. Here we report potent selective lead small molecule, AVI-4206, effective model infection. Cellular models indicate AVI-4206 has high target engagement weakly inhibit gamma interferon- catalytic activity-dependent manner; stronger antiviral effect for observed human airway organoids. In animal severe infection, reduces replication, potentiates responses, leads survival benefit. Our results provide pharmacological proof concept valid therapeutic via novel immune-restoring mechanism could potentially synergize with existing therapies targeting distinct, essential aspects life cycle. This approach more widely used other macrodomains develop beyond COVID-19.

Language: Английский

Citations

0
Synthesis of Structural ADP-Ribose Analogues as Inhibitors for SARS-CoV-2 Macrodomain 1 DOI Creative Commons

Koen J. Rijpkema,

M. Schuller,

Miriam S. van der Veer

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(27), P. 5700 - 5704

Published: June 27, 2024

Protein adenosine diphosphate (ADP)-ribosylation is crucial for a proper immune response. Accordingly, viruses have evolved ADP-ribosyl hydrolases to remove these modifications, prominent example being the SARS-CoV-2 NSP3 macrodomain, "Mac1". Consequently, inhibitors are developed by testing large libraries of small molecule candidates, with considerable success. However, relatively underexplored angle in design pertains synthesis structural substrate mimics. Here, we present and biophysical activity novel ribose (ADPr) analogues as Mac1 inhibitors.

Language: Английский

Citations

1
1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit DOI Open Access
Jozef Nahálka

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4440 - 4440

Published: April 18, 2024

The COVID-19 pandemic prompted rapid research on SARS-CoV-2 pathogenicity. Consequently, new data can be used to advance the molecular understanding of infection. present bioinformatics study discusses "spikeopathy" at level and focuses possible post-transcriptional regulation spike protein S1 subunit in host cell/tissue. A theoretical protein-RNA recognition code was check compatibility with mRNAs human transcriptome (1-L transcription). principle for this method is elucidated defined RNA binding GEMIN5 (gem nuclear organelle-associated 5) RNU2-1 (U2 spliceosomal RNA). Using described here, it shown that 45% genes/proteins identified by 1-L transcription are directly linked COVID-19, 39% indirectly 16% cannot currently associated COVID-19. stroke, diabetes, cardiac injury.

Language: Английский

Citations

1
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

et al.

Published: Oct. 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.

Language: Английский

Citations

0