Etienne Decroly

Etienne Decroly
French National Centre for Scientific Research | CNRS · Architecture et Fonction des Macromolécules Biologiques

Professor

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175
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Introduction
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Publications

Publications (175)
Article
Enzymes involved in RNA capping of SARS-CoV-2 are essential for the stability of viral RNA, translation of mRNAs, and virus evasion from innate immunity, making them attractive targets for antiviral agents. In this work, we focused on the design and synthesis of nucleoside-derived inhibitors against the SARS-CoV-2 nsp14 (N7-guanine)-methyltransfera...
Article
The spike protein (S) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directs infection of the lungs and other tissues following its binding to the angiotensin-converting enzyme 2 (ACE2) receptor. For effective infection, the S protein is cleaved at two sites: S1/S2 and S2'. The "priming" of the surface S protein at S1/S2 (PRRAR685↓...
Research Proposal
Full-text available
It is essential to examine all plausible hypotheses regarding the origin of COVID-19, in order to understand how this pandemic started and prevent future pandemics. The unfortunate reality is that this process has been stalled. The European Commission could play a decisive role in addressing this critical issue of European and global concern with t...
Article
Full-text available
Effective drugs against SARS-CoV-2 are urgently needed to treat severe cases of infection and for prophylactic use. The main viral protease (nsp5 or 3CLpro) represents an attractive and possibly broad-spectrum target for drug development as it is essential to the virus life cycle and highly conserved among betacoronaviruses. Sensitive and efficient...
Article
Full-text available
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has led to a pandemic, that continues to be a huge public health burden. Despite the availability of vaccines, there is still a need for small-molecule antiviral drugs. In an effort to identify novel and drug-like hit matter that can be used for subse...
Article
Full-text available
The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymeras...
Article
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Enteroviruses are globally prevalent human pathogens responsible for many diseases. The nonstructural protein 2C is a AAA+ helicase and plays a key role in enterovirus replication. Drug repurposing screens identified 2C-targeting compounds such as fluoxetine and dibucaine, but how they inhibit 2C is unknown. Here, we present a crystal structure of...
Article
Full-text available
As coronaviruses (CoVs) replicate in the host cell cytoplasm, they rely on their own capping machinery to ensure the efficient translation of their messenger RNAs (mRNAs), protect them from degradation by cellular 5′ exoribonucleases (ExoNs), and escape innate immune sensing. The CoV nonstructural protein 14 (nsp14) is a bifunctional replicase subu...
Preprint
The Spike (S)-protein of SARS-CoV-2 binds host-cell receptor ACE2 and requires proteolytic “priming” at P R RA R 685 ↓ into S1 and S2 (cleavage at S1/S2), and “fusion-activation” at KPS KR 815 ↓ (cleavage at S2’) for viral entry. Both cleavages occur at Furin-like motifs suggesting that proprotein convertases might promote virus entry. In vitro Fur...
Article
The worldwide circulation of different viruses coupled with the increased frequency and diversity of new outbreaks, strongly highlight the need for new antiviral drugs to quickly react against potential pandemic pathogens. Broad-spectrum antiviral agents (BSAAs) represent the ideal option for a prompt response against multiple viruses, new and re-e...
Preprint
Full-text available
A worldwide effort is ongoing to discover drugs against the Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2), which has so far caused >3.5 million fatalities (https://covid19.who.int/). The virus essential RNA-dependent RNA polymerase complex is targeted by several nucleoside/tide analogues whose mechanisms of action and clinical p...
Article
With sizes <50 kb, viral RNA genomes are at the crossroads of genetic, biophysical, and biochemical stability in their host cell. Here, we analyze the enzymatic assets accompanying large RNA genome viruses, mostly based on recent scientific advances in Coronaviridae. We argue that, in addition to the presence of an RNA exonuclease (ExoN), two marke...
Article
Venezuelan equine encephalitis virus (VEEV) is a re-emerging arthropod-borne virus causing encephalitis in humans and domesticated animals. VEEV possesses a positive single-stranded RNA genome capped at its 5'-end. The capping process is performed by the non-structural protein nsP1, which bears methyl and guanylyltransferases activities. The cappin...
Preprint
Full-text available
As coronaviruses (CoVs) replicate in the host cell cytoplasm, they rely on their own capping machinery to ensure the efficient translation of their mRNAs, protect them from degradation by cellular 5’ exoribonucleases, and escape innate immune sensing. The CoV nonstructural protein 14 (nsp14) is a bi-functional replicase subunit harboring an N-termi...
Preprint
Full-text available
One year after the onset of the COVID-19 pandemic, the origin of SARS-CoV-2 still eludes humanity. Early publications firmly stated that the virus was of natural origin, and the possibility that the virus might have escaped from a lab was discarded in most subsequent publications. However, based on a re-analysis of the initial arguments, highlighte...
Article
Full-text available
Respiratory syncytial virus (RSV) is a negative sense single-stranded RNA virus and one of the main causes of severe lower respiratory tract infections in infants and young children. RSV RNA replication/transcription and capping are ensured by the viral Large (L) protein. The L protein contains a polymerase domain associated with a polyribonucleoti...
Research Proposal
Full-text available
We call on the World Health Organization and its Executive Board to fully address the recommendations and questions raised in this letter as a critical step toward protecting everyone on earth and future generations. As terrible as COVID-19 has been, this is almost certainly not the last pandemic we will face -- and possibly not even the worst. Ta...
Preprint
Full-text available
The enterovirus genus encompasses many clinically important human pathogens such as poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses and rhinoviruses. These viruses are the etiological agents of several human diseases, including hand-foot-and-mouth disease, neonatal sepsis, encephalitis, meningitis, paralysis and respiratory infect...
Preprint
Full-text available
Viral exoribonucleases are uncommon in the world of RNA viruses. To date, this activity has been identified only in the Arenaviridae and the Coronaviridae families. These exoribonucleases play important but different roles in both families: for mammarenaviruses the exoribonuclease is involved in the suppression of the host immune response whereas f...
Preprint
Full-text available
How viruses from the Coronaviridae family initiate viral RNA synthesis is unknown. Here we show that the SARS-CoV-1 and -2 Nidovirus RdRp-Associated Nucleotidyltransferase (NiRAN) domain on nsp12 uridylates the viral cofactor nsp8, forming a UMP-Nsp8 covalent intermediate that subsequently primes RNA synthesis from a poly(A) template; a protein-pri...
Research Proposal
Full-text available
As strong supporters of the WHO and its mission, we believe it must be made clear that any findings of the joint committee, while potentially useful to a limited extent, represent neither the official position of the WHO nor the result of an unrestricted, independent investigation. For this reason, we believe it is essential that the contours of a...
Article
Full-text available
SARS-CoV-2 is a new human coronavirus (CoV), which emerged in China in late 2019 and is responsible for the global COVID-19 pandemic that caused more than 97 million infections and 2 million deaths in 12 months. Understanding the origin of this virus is an important issue, and it is necessary to determine the mechanisms of viral dissemination in or...
Preprint
Full-text available
This letter was submitted to The Lancet on January 6, 2021. It re-evaluates the scientific evidences that have been invoked at the very beginning of the COVID-19 pandemics to support the hypothesis of a natural zoonosis, and shows that these arguments were inconclusive and felt under some logical flaws. It thus requests scientific journals to open...
Article
The Ebola virus is a deadly human pathogen responsible for several outbreaks in Africa. Its genome encodes the “large” L protein, an essential enzyme that has polymerase, capping and methyltransferase activities. The methyltransferase activity leads to RNA co-transcriptional modifications at the N7 position of the cap structure and at the 2’O posit...
Preprint
Full-text available
The spîke (S)-protein of SARS-CoV-2 binds ACE2 and requires proteolytic “priming” at P R RA R 685 ↓ into S1 and S2 (cleavage at S1/S2), and “fusion-activation” at a S2’ site for viral entry. In vitro , Furin cleaved peptides mimicking the S1/S2 cleavage site more efficiently than at the putative S2’, whereas TMPRSS2 inefficiently cleaved both sites...
Article
Full-text available
English translation of a French manuscript to be published in the August-Sept 2020 issue of Médecine/Sciences.
Article
Full-text available
The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We...
Preprint
Full-text available
SARS-CoV-2 is a new human coronavirus (CoV) which emerged in China in late 2019 and is responsible for the global COVID-19 pandemic that caused more than 340,000 deaths in four months. Understanding the origin of this virus is an important issue and it is necessary to determine the mechanisms of its dissemination in order to contain future epidemic...
Article
Full-text available
Le SARS-CoV-2 est un nouveau coronavirus (CoV) humain. Il a émergé en Chine fin 2019 et est responsable de la pandémie mondiale de Covid-19 qui a causé plus de 540 000 décès en six mois. La compréhension de l’origine de ce virus est une question importante et il est nécessaire de déterminer les mécanismes de sa dissémination afin de pouvoir se prém...
Article
Full-text available
A novel coronavirus, named SARS-CoV-2, emerged in 2019 in China and rapidly spread worldwide. As no approved therapeutics exists to treat COVID-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time-consuming s...
Article
Various studies have shown that NS5 RNA methyltransferase (MTase) is a key enzyme involved in mRNA capping, a step crucial for flaviviral replication. Therefore, it has been identified as a potential target for therapeutic intervention in infections arising due to flaviviruses. In this paper, we report computer-assisted design of 2,3-dioxopyrrolidi...
Article
Alphaviruses are arthropod-borne viruses of public health concern. To date no efficient vaccine nor antivirals are available for safe human use. During viral replication the nonstructural protein 1 (nsP1) catalyzes capping of genomic and subgenomic RNAs. The capping reaction is unique to the Alphavirus genus. The whole three-step process follows a...
Article
Flaviviruses, such as Dengue (DENV) and Zika (ZIKV) viruses, represent a severe health burden. There are currently no FDA-approved treatments, and vaccines against most flaviviruses are still lacking. We have developed several flexible analogues (“fleximers”) of the FDA-approved nucleoside Acyclovir that exhibit activity against various RNA viruses...
Article
The health emergency caused by the recent Covid-19 pandemic highlights the need to identify effective treatments against the virus causing this disease (SARS-CoV-2). The first clinical trials have been testing repurposed drugs that show promising anti-SARS-CoV-2 effects in cultured cells. Although more than 2400 clinical trials are already under wa...
Preprint
Full-text available
Abstract : SARS-CoV-2 is a new human coronavirus (CoV), which emerged in China in late 2019 and is responsible for the global COVID-19 pandemic that caused more than 540,000 deaths in six months. Understanding the origin of this virus is an important issue and it is necessary to determine the mechanisms of its dissemination in order to contain futu...
Preprint
Full-text available
Abstract : SARS-CoV-2 is a new human coronavirus (CoV), which emerged in China in late 2019 and is responsible for the global COVID-19 pandemic that caused more than 540,000 deaths in six months. Understanding the origin of this virus is an important issue and it is necessary to determine the mechanisms of its dissemination in order to contain futu...
Article
In December 2019, a new coronavirus was identified in the Hubei province of central china and named SARS-CoV-2. This new virus induces COVID-19, a severe respiratory disease with high death rate. A putative target to interfere with the virus is the host transmembrane serine protease family member II (TMPRSS2). This enzyme is critical for the entry...
Article
Full-text available
The spreading of new viruses is known to provoke global human health threat. The current COVID-19 pandemic caused by the recently emerged coronavirus SARS-CoV-2 is one significant and unfortunate example of what the world will have to face in the future with emerging viruses in absence of appropriate treatment. The discovery of potent and specific...
Preprint
Full-text available
The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. He...
Preprint
Full-text available
In December 2019, a new coronavirus was identified in the Hubei province of central china and named SRAS-CoV-2. This new virus induces COVID-19, a severe respiratory disease with high death rate. The spike protein (S) of SARS-CoV-2 contains furin-like cleavage sites absent the other SARS-like viruses. The viral infection requires the priming or cle...
Article
Despite the worldwide re-emergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. We here aim to identify the target of a novel class of CHIKV inhibitors i.e. CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 5...
Article
The large (L) protein of Ebola virus is a key protein for virus replication. Its N-terminal region harbors the RNA-dependent RNA polymerase activity, and its C-terminus contains a cap assembling line composed of a capping domain and a methyltransferase domain (MTase) followed by a C-terminal domain (CTD) of unknown function. The L protein MTase cat...
Preprint
Full-text available
A novel coronavirus, named SARS-CoV-2, emerged in 2019 from Hubei region in China and rapidly spread worldwide. As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass th...
Article
The rapid global emergence of SARS-CoV-2 has been the cause of significant health concern, highlighting the immediate need for antivirals. Viral RNA-dependent RNA polymerases (RdRp) play essential roles in viral RNA synthesis, and thus remains the target of choice for the prophylactic or curative treatment of several viral diseases, due to high seq...
Article
Full-text available
The order Nidovirales is a diverse group of (+)RNA viruses, classified together based on their common genome organisation and conserved replicative enzymes, despite drastic differences in size and complexity. One such difference pertains to the mechanisms and enzymes responsible for generation of the proposed viral 5′ RNA cap. Within the Coronaviri...
Article
Full-text available
In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the o...
Article
Full-text available
The recent outbreaks of Zika virus (ZIKV) infection worldwide make the discovery of novel antivirals against flaviviruses a research priority. This work describes the identification of novel inhibitors of ZIKV through a structure-based virtual screening approach using the ZIKV NS5-MTase. A novel series of molecules with a carbazoyl-aryl-urea struct...
Article
Viral RNA 2’‐O‐methyltransferases play a crucial role for luring the host cell innate antiviral response during a viral infection by catalyzing either the methylation of the 5’‐end RNA cap‐structure at 2’‐OH of nucleoside N1 or by inducing internal 2’‐O‐methylation of adenosines within RNA sequence using S‐adenosyl‐L‐methionine (SAM) as the methyl...
Article
Numerous interventions are in clinical development for respiratory syncytial virus (RSV) infection, including small molecules that target viral transcription and replication. These processes are catalyzed by a complex comprising the RNA-dependent RNA polymerase (L) and the tetrameric phosphoprotein (P). RSV P recruits multiple proteins to the polym...
Preprint
Full-text available
Members of the Nidovirales order have (+)RNA genomes amongst the largest in size in the RNA virus world. Expression of their genes is promoted through reading of genomic RNA and mRNA transcripts by the ribosome of the infected cell. The 5'-end of these RNAs is supposedly protected by an RNA-cap structure (m7GpppNm) whose most synthesis steps remain...
Article
Full-text available
Most eukaryotic expression systems make use of host-cell nuclear transcriptional and post-transcriptional machineries. Here, we present the first generation of the chimeric cytoplasmic capping-prone phage polymerase (C3P3-G1) expression system developed by biological engineering, which generates capped and polyadenylated transcripts in host-cell cy...
Article
Full-text available
In mammals, 2′-O-methylation of RNA is a molecular signature by which the cellular innate immune system distinguishes endogenous from exogenous messenger RNA1–3. However, the molecular functions of RNA 2′-O-methylation are not well understood. Here we have purified TAR RNA-binding protein (TRBP) and its interacting partners and identified a DICER-i...
Article
Les mononégavirus, comme le virus Ebola, codent pour une protéine L (large) qui possède toutes les activités enzymatiques nécessaires au cycle de réplication/transcription et de coiffage des ARNs. La région conservée VI (CRVI) du domaine C-terminal de la protéine L présente une tétrade catalytique K-D-K-E typique des 2'O méthyltransférases (MTase)....