Human coronaviruses: activation and antagonism of innate immune responses DOI
Nikhila S. Tanneti, Helen A. Stillwell, Susan R. Weiss

et al.

Microbiology and Molecular Biology Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

SUMMARY Human coronaviruses cause a range of respiratory diseases, from the common cold (HCoV-229E, HCoV-NL63, HCoV-OC43, and SARS-CoV-2) to lethal pneumonia (SARS-CoV, SARS-CoV-2, MERS-CoV). Coronavirus interactions with host innate immune antiviral responses are an important determinant disease outcome. This review compares host’s response different human coronaviruses. Host defenses discussed in this include frontline against viruses nasal epithelium, early sensing viral infection by effectors, double-stranded RNA stress-induced pathways, antagonism conferred conserved coronavirus nonstructural proteins genus-specific accessory proteins. The HCoV-229E -NL63 induce robust interferon signaling related SARS-CoV SARS-CoV-2 intermediate levels activation, MERS-CoV shuts down these pathways almost completely.

Language: Английский

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

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

Language: Английский

Citations

5
Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning DOI Creative Commons
G.J. Correy, Moira Rachman, Takaya Togo

et al.

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

Published: Aug. 26, 2024

The macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block could be a new therapeutic strategy suppression. We previously performed large-scale X-ray crystallography-based fragment screen discovered sub-micromolar inhibitor by linking. However, this carboxylic acid-containing lead had poor membrane permeability other liabilities made optimization difficult. Here, we developed shape-based virtual screening pipeline - FrankenROCS to identify inhibitors using crystal structures. used exhaustively Enamine high-throughput (HTS) collection of 2.1 million compounds selected 39 testing, with most potent compound having an IC

Language: Английский

Citations

4
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
Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response DOI Creative Commons
Alpha A. Lee,

Isabelle Amick,

Jasmin C. Aschenbrenner

et al.

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

Published: Aug. 21, 2024

Abstract A strategy for pandemic preparedness is the development of antivirals against a wide set viral targets with complementary mechanisms action. SARS-CoV-2 nsp3-mac1 macrodomain ADP-ribosylhydrolase activity, which counteracts host immune response. Targeting virus’ immunomodulatory functionality offers differentiated to inhibit compared approved therapeutics, target replication directly. Here we report fragment-based lead generation campaign guided by computational approaches. We discover tool compounds activity at low nanomolar concentrations, and responsive structure-activity relationships, high selectivity, drug-like properties. Using our inhibitors, show that inhibition increases ADP-ribosylation, but surprisingly does not translate demonstrable antiviral in cell culture iPSC-derived pneumocyte models. Further, no synergistic observed combination interferon gamma, main protease inhibitor, nor papain-like inhibitor. Our results question extent targeting modulation innate immunity-driven ADP-ribosylation can influence replication. Moreover, these findings suggest might be suitable therapeutics development.

Language: Английский

Citations

2
GS-441524-Diphosphate-Ribose Derivatives as Nanomolar Binders and Fluorescence Polarization Tracers for SARS-CoV-2 and Other Viral Macrodomains DOI Creative Commons
Kewen Peng,

Shamar D. Wallace,

Saket R. Bagde

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(5), P. 1093 - 1105

Published: April 22, 2024

Viral macrodomains that can bind to or hydrolyze protein adenosine diphosphate ribosylation (ADP-ribosylation) have emerged as promising targets for antiviral drug development. Many inhibitor development efforts been directed against the severe acute respiratory syndrome coronavirus 2 macrodomain 1 (SARS-CoV-2 Mac1). However, potent inhibitors viral are still lacking, with best in micromolar range. Based on GS-441524, a remdesivir precursor, and our previous studies, we designed synthesized binders of SARS-CoV-2 Mac1 other including those Middle East (MERS-CoV), Venezuelan equine encephalitis virus (VEEV), Chikungunya (CHIKV). We show 1′-CN group GS-441524 promotes binding all four tested while capping 1″-OH GS-441524-diphosphate-ribose simple phenyl ring further contributes binding. Incorporating these two structural features, 20- 6000-fold increases affinity over ADP-ribose SARS-CoV-2, MERS-CoV, VEEV, CHIKV macrodomains. Moreover, building binders, developed highly sensitive fluorescence polarization tracers only require nanomolar proteins effectively resolve affinities inhibitors. Our findings probes described here will facilitate future more

Language: Английский

Citations

1
Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection DOI Creative Commons
Zhenyu Zhang, Isabel Uribe,

Kaitlin A. Davis

et al.

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

Published: Sept. 19, 2024

SUMMARY ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization turnover. Here we show influenza A virus infection causes rapid dramatic upregulation of global inhibits viral replication. Mass spectrometry defined for the first time ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 sites on ∼1,080 host proteins, as well over 100 proteins. Our data indicate increase likely reflects change in form rather than new targets. Functional assays demonstrated replication machinery antagonizes its activity further revealed anti-viral PARPs counteracted NS1, assigning to primary antagonist innate immunity. We identified PARP1 enzyme producing majority present infection. Influenza replicated faster cells lacking PARP1, linking phenotype. Together, these establish immune-like response antagonized previously unknown NS1.

Language: Английский

Citations

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

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
Human coronaviruses: activation and antagonism of innate immune responses DOI
Nikhila S. Tanneti, Helen A. Stillwell, Susan R. Weiss

et al.

Microbiology and Molecular Biology Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

SUMMARY Human coronaviruses cause a range of respiratory diseases, from the common cold (HCoV-229E, HCoV-NL63, HCoV-OC43, and SARS-CoV-2) to lethal pneumonia (SARS-CoV, SARS-CoV-2, MERS-CoV). Coronavirus interactions with host innate immune antiviral responses are an important determinant disease outcome. This review compares host’s response different human coronaviruses. Host defenses discussed in this include frontline against viruses nasal epithelium, early sensing viral infection by effectors, double-stranded RNA stress-induced pathways, antagonism conferred conserved coronavirus nonstructural proteins genus-specific accessory proteins. The HCoV-229E -NL63 induce robust interferon signaling related SARS-CoV SARS-CoV-2 intermediate levels activation, MERS-CoV shuts down these pathways almost completely.

Language: Английский

Citations

0