A5014411567- Enzyme Structure and Function
- SARS-CoV-2 and COVID-19 Research
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Enzyme Production and Characterization
- Microbial Natural Products and Biosynthesis
- RNA and protein synthesis mechanisms
- Microbial Metabolites in Food Biotechnology
- Peptidase Inhibition and Analysis
- Biochemical and Molecular Research
- Asymmetric Hydrogenation and Catalysis
- Food Quality and Safety Studies
- Pharmacogenetics and Drug Metabolism
- Genomics and Phylogenetic Studies
- Metalloenzymes and iron-sulfur proteins
- Microbial metabolism and enzyme function
- Calcium Carbonate Crystallization and Inhibition
- Plant biochemistry and biosynthesis
- interferon and immune responses
- Biofuel production and bioconversion
- Hepatitis C virus research
- Microbial Metabolic Engineering and Bioproduction
- Metal-Catalyzed Oxygenation Mechanisms
- RNA modifications and cancer
- Porphyrin Metabolism and Disorders
Oak Ridge National Laboratory
2020-2023
National Energy Technology Laboratory
2020-2023
United States Department of Energy
2020-2022
The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is main protease 3CL M
Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (Mpro) is critical for virus replication thus considered attractive drug target. We performed design characterization three covalent hybrid inhibitors BBH-1, BBH-2 NBH-2 created by splicing components hepatitis C boceprevir narlaprevir, known SARS-CoV-1 inhibitors. A joint X-ray/neutron structure...
Abstract Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 essential for viral replication. In addition, PLpro dysregulates the host immune response cleaving ubiquitin and interferon-stimulated gene 15 protein proteins. As a result, promising target inhibition small-molecule therapeutics. Here we design series...
The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses unusual catalytic dyad composed Cys145 and His41 residues. A critical question in field has been what protonation states ionizable residues substrate-binding active-site cavity are; resolving this point would help understand details inform rational drug development against pernicious virus. Here, we present room-temperature neutron structure Mpro,...
The emergence of the novel coronavirus SARS-CoV-2 has resulted in a worldwide pandemic not seen generations. Creating treatments and vaccines to battle COVID-19, disease caused by virus, is paramount importance order stop its spread save lives. viral main protease, 3CL M pro , indispensable for replication therefore an important target design specific protease inhibitors. Detailed knowledge structure function crucial guide structure-aided computational drug-design efforts. Here, oxidation...
The main protease (3CL Mpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it attractive drug target. To date, small-molecule clinical drugs are available specifically inhibit SARS-CoV-2 Mpro. aid rational design, we determined a neutron structure of Mpro in complex α-ketoamide inhibitor telaprevir at near-physiological (22 °C) temperature. We directly observed...
The nonstructural protein 3 (NSP3) macrodomain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Mac1) removes adenosine diphosphate (ADP) ribosylation posttranslational modifications, playing a key role in the immune evasion capabilities virus responsible for disease 2019 pandemic. Here, we determined neutron and x-ray crystal structures SARS-CoV-2 NSP3 using multiple forms, temperatures, pHs, across apo ADP-ribose–bound states. We characterize extensive solvation Mac1 active...
Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle disease 2019 (COVID-19). SARS-CoV-2 main protease (Mpro) an established drug target the design of inhibitors. We performed a structure–activity relationship (SAR) study noncovalent compounds that bind in enzyme's substrate-binding subsites S1 and S2, revealing structural, electronic, electrostatic determinants these sites. The was guided by X-ray/neutron...
Direct-acting antivirals for the treatment of COVID-19 pandemic caused by SARS-CoV-2 virus are needed to complement vaccination efforts. Given ongoing emergence new variants, automated experimentation, and active learning based fast workflows antiviral lead discovery remain critical our ability address pandemic's evolution in a timely manner. While several such pipelines have been introduced discover candidates with noncovalent interactions main protease (Mpro), here we developed closed-loop...
The replication of SARS-CoV-2 produces two large polyproteins, pp1a and pp1ab, that are inactive until cleavage by the viral chymotrypsin-like cysteine protease enzyme (3CL M pro ) into a series smaller functional proteins. At heart 3CL is an unusual catalytic dyad formed side chains His41 Cys145 coordinated water molecule. mechanism which operates still unknown, as crucial information on protonation states within active site unclear. To experimentally determine other residues in...
Papain-like protease (PLpro) from SARS-CoV-2 plays essential roles in the replication cycle of virus. In particular, it preferentially interacts with and cleaves human interferon-stimulated gene 15 (hISG15) to suppress innate immune response host. We used small-angle X-ray neutron scattering combined computational techniques study mechanism interaction PLpro hISG15. showed that hISG15 undergoes a transition an extended compact state after binding PLpro, conformation has not been previously...
Abstract The COVID-19 disease caused by the SARS-CoV-2 Coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is main protease 3CL M pro due to its essential role in processing polyproteins translated from viral RNA. Here we report room temperature X-ray structure of unliganded , revealing resting active site and conformation catalytic cavity. Comparison with previously reported low-temperature ligand-free inhibitor-bound structures suggest that may...
Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 essential for viral replication. In addition, PLpro dysregulates the host immune response cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) proteins. As a result, promising target inhibition small-molecule therapeutics. Here we have designed series...
Direct-acting antivirals are needed to combat coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The papain-like protease (PLpro) domain of Nsp3 from SARS-CoV-2 essential for viral replication. In addition, PLpro dysregulates the host immune response cleaving ubiquitin and interferon-stimulated gene 15 protein (ISG15) proteins. As a result, promising target inhibition small-molecule therapeutics. Here we have designed series...
Abstract The COVID-19 pandemic continues to disrupt everyday life, with constantly emerging SARS-CoV-2 variants threatening render current vaccines ineffective. Small-molecule antivirals can provide an important therapeutic treatment option that is subject challenges caused by the virus variants. viral main protease (M pro ) critical for replication and thus considered attractive drug target specific inhibitors. We performed design characterization of three reversible covalent hybrid...
The NSP3 macrodomain of SARS CoV 2 (Mac1) removes ADP-ribosylation post-translational modifications, playing a key role in the immune evasion capabilities virus responsible for COVID-19 pandemic. Here, we determined neutron and X-ray crystal structures SARS-CoV-2 using multiple forms, temperatures, pHs, across apo ADP-ribose-bound states. We characterize extensive solvation Mac1 active site, visualize how water networks reorganize upon binding ADP-ribose non-native ligands, inspiring...
Abstract The main protease (3CL M pro ) from SARS-CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication, possessing unusual catalytic dyad composed His41 and Cys145. A long-standing question in field has been what protonation states ionizable residues substrate-binding active site cavity are. Here, we present room-temperature neutron structure 3CL which allows direct determination hydrogen atom positions and, hence, states. natively adopts a zwitterionic...