Cited by Discovery of potent SARS-CoV-2 nsp3 macrodomain inhibitors uncovers lack of translation to cellular antiviral response

ADP-ribosylation from molecular mechanisms to therapeutic implications DOI

Marcin J. Suskiewicz, Evgeniia Prokhorova, J.G.M. Rack

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(21), P. 4475 - 4495

Published: Oct. 1, 2023

ADP-ribosylation is a ubiquitous modification of biomolecules, including proteins and nucleic acids, that regulates various cellular functions in all kingdoms life. The recent emergence new technologies to study has reshaped our understanding the molecular mechanisms govern establishment, removal, recognition this modification, as well its impact on organismal function. These advances have also revealed intricate involvement human physiology pathology enormous potential their manipulation holds for therapy. In review, we present state-of-the-art findings covering work structural biology, biochemistry, cell clinical aspects ADP-ribosylation.

Language: Английский

Citations

SARS-CoV-2 and innate immunity: the good, the bad, and the “goldilocks” DOI

Benjamín L. Sievers, Mark T. K. Cheng,

Kata Csiba

et al.

Cellular and Molecular Immunology, Journal Year: 2023, Volume and Issue: 21(2), P. 171 - 183

Published: Nov. 20, 2023

Abstract An ancient conflict between hosts and pathogens has driven the innate adaptive arms of immunity. Knowledge about this interplay can not only help us identify biological mechanisms but also reveal pathogen vulnerabilities that be leveraged therapeutically. The humoral response to SARS-CoV-2 infection been focus intense research, role immune system received significantly less attention. Here, we review current knowledge various means employs evade defense systems. We consider immunity in vaccines phenomenon long COVID.

Language: Английский

Citations

SARS-CoV-2 nsp15 endoribonuclease antagonizes dsRNA-induced antiviral signaling DOI

Clayton J. Otter, Nicole Bracci, Nicholas A. Parenti

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(15)

Published: April 3, 2024

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has caused millions of deaths since its emergence in 2019. Innate immune antagonism by lethal CoVs such as SARS-CoV-2 is crucial for optimal replication and pathogenesis. The conserved nonstructural protein 15 (nsp15) endoribonuclease (EndoU) limits activation double-stranded (ds)RNA-induced pathways, including interferon (IFN) signaling, kinase R (PKR), oligoadenylate synthetase/ribonuclease L (OAS/RNase L) during diverse CoV infections murine Middle East (MERS)-CoV. To determine how nsp15 functions infection, we constructed a recombinant (nsp15

Language: Английский

Citations

PARP14 and PARP9/DTX3L regulate interferon-induced ADP-ribosylation DOI

Pulak Kar,

Chatrin Chatrin, N Mimica Dukic

et al.

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(14), P. 2929 - 2953

Published: June 4, 2024

Language: Английский

Citations

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

A single inactivating amino acid change in the SARS-CoV-2 NSP3 Mac1 domain attenuates viral replication in vivo DOI

Taha Y. Taha,

Rahul K. Suryawanshi,

Irene P. Chen

et al.

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(8), P. e1011614 - e1011614

Published: Aug. 31, 2023

Despite unprecedented efforts, our therapeutic arsenal against SARS-CoV-2 remains limited. The conserved macrodomain 1 (Mac1) in NSP3 is an enzyme exhibiting ADP-ribosylhydrolase activity and a possible drug target. To determine the role of Mac1 catalytic viral replication, we generated recombinant viruses replicons encoding catalytically inactive domain by mutating critical asparagine active site. While substitution to alanine (N40A) reduced ~10-fold, mutations aspartic acid (N40D) ~100-fold relative wild-type. Importantly, N40A mutation rendered unstable vitro lowered expression levels bacterial mammalian cells. When incorporated into molecular clones, N40D mutant only modestly affected fitness immortalized cell lines, but replication human airway organoids 10-fold. In mice, replicated at >1000-fold lower compared wild-type virus while inducing robust interferon response; all animals infected with survived infection. Our data validate as promising target develop antivirals.

Language: Английский

Citations

Anti-viral defense by an ADP-ribosyltransferase that targets mRNA to block translation DOI

Christopher N. Vassallo, Christopher R. Doering, Michael T. Laub

et al.

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

Published: Feb. 24, 2024

Abstract Host-pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution sophisticated mechanisms throughout biology, including in bacteria that must evade their viral predators known as bacteriophages. Here, we characterize a widely distributed anti-phage defense system, CmdTAC, provides robust against infection by T-even family phages. Our results support model which CmdC detects sensing capsid proteins, ultimately leading activation toxic ADP-ribosyltransferase effector protein, CmdT. We show newly synthesized protein triggers dissociation chaperone from CmdTAC complex, destabilization and degradation antitoxin CmdA, with consequent liberation CmdT ADP-ribosyltransferase. Strikingly, does not target DNA, or structured RNA, targets other ADP-ribosyltransferases. Instead, modifies N6 position adenine GA dinucleotides within single-stranded RNAs arrest mRNA translation inhibition replication. work reveals new mechanism anti-viral previously unknown but broadly class ADP-ribosyltransferases mRNA.

Language: Английский

Citations

Mutation of a highly conserved isoleucine residue in loop 2 of several 𝛽-coronavirus macrodomains indicates that enhanced ADP-ribose binding is detrimental to infection DOI

Catherine M. Kerr, Jessica J. Pfannenstiel, Yousef M. Alhammad

et al.

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

Published: Jan. 4, 2024

All coronaviruses (CoVs) encode for a conserved macrodomain (Mac1) located in nonstructural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that binds and hydrolyzes mono-ADP-ribose from target proteins. Previous work has shown important virus replication pathogenesis. Within Mac1, there are several regions highly across CoVs, including the GIF (glycine-isoleucine-phenylalanine) motif. To determine how biochemical activities of these residues impact CoV replication, isoleucine phenylalanine were mutated to alanine (I-A/F-A) both recombinant proteins murine hepatitis (MHV), Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute 2 (SARS-CoV-2). The F-A mutant had ADP-ribose binding and/or hydrolysis defects led attenuated pathogenesis cell culture mice. In contrast, I-A mutations normal enzyme activity enhanced binding. Despite increased binding, MERS-CoV SARS-CoV-2 mice, indicating this residue acts as gate controls efficient replication. These results highlight function provide unique insight into macrodomains control promote viral

Language: Английский

Citations

PARP14 is pro- and anti-viral host factor that promotes IFN production and affects the replication of multiple viruses DOI

Srivatsan Parthasarathy,

Pradtahna Saenjamsai,

Hongping Hao

et al.

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

Published: April 26, 2024

ABSTRACT PARP14 is a 203 kDa multi-domain protein that primarily known as an ADP-ribosyltransferase, and involved in variety of cellular functions including DNA damage, microglial activation, inflammation, cancer progression. In addition, upregulated by interferon (IFN), indicating role the antiviral response. Furthermore, has evolved under positive selection, again it host-pathogen conflict. We found required for increased IFN-I production response to coronavirus infection lacking ADP-ribosylhydrolase (ARH) activity poly(I:C), however, whether direct function remains unclear. Here we demonstrate catalytic enhances IFN-III responses restricts ARH-deficient murine hepatitis virus (MHV) severe acute respiratory syndrome 2 (SARS-CoV-2) replication. To determine if PARP14’s extended beyond CoVs, tested ability herpes simplex 1 (HSV-1) several negative-sense RNA viruses, vesicular stomatitis (VSV), Ebola (EBOV), Nipah (NiV), infect A549 knockout (KO) cells. HSV-1 had replication KO cells, contrast, was critical efficient VSV, EBOV, NiV, with EBOV infectivity at less than 1% WT A active site inhibitor no impact on or infection, its effect these viruses independent activity. These data promotes IFN both pro– anti-viral targeting multiple viruses. IMPORTANCE The largely regulated post-translation modifications (PTM), ADP-ribosylation. ADP-ribosyltransferase However, been described PARP14. Here, represses replication, demonstrating functions. Surprisingly, also pro-viral functions, which have high mortality are pandemic potential. indicate potential therapeutic target highly pathogenic

Language: Английский

Citations

The Mac1 ADP-ribosylhydrolase is a Therapeutic Target for SARS-CoV-2 DOI

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