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Book: Dengue and Zika

Hilgenfeld, Rolf / Vasudevan, Subhash G.

control and antiviral treatment strategies

(Advances in experimental medicine and biology ; 1062)

2018

Author's details	Rolf Hilgenfeld, Subhash G. Vasudevan editors
Series title	Advances in experimental medicine and biology ; 1062
Collection
Keywords	Licensed vaccine ; Efficacious drugs ; Vector control ; Antivirals ; Protective efficacy
Subject code	570
Language	English
Size	xiii, 375 Seiten, Illustrationen, 25.4 cm x 17.8 cm
Publisher	Springer
Publishing place	Singapore
Publishing country	Singapore
Document type	Book
HBZ-ID	HT019717303
ISBN	978-981-10-8726-4 ; 981-10-8726-1 ; 9789811087271 ; 981108727X
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Zika virus NS1, a pathogenicity factor with many faces.

Hilgenfeld, Rolf

The EMBO journal

2016 Volume 35, Issue 24, Page(s) 2631–2633

Language	English
Publishing date	2016-12-15
Publishing country	England
Document type	Journal Article
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.201695871
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Therapeutic strategies for COVID-19: progress and lessons learned.

Li, Guangdi / Hilgenfeld, Rolf / Whitley, Richard / De Clercq, Erik

Nature reviews. Drug discovery

2023 Volume 22, Issue 6, Page(s) 449–475

Abstract: The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic strategies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or human proteins to control viral infection, encompassing ... ...

Abstract	The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic strategies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or human proteins to control viral infection, encompassing hundreds of potential drugs and thousands of patients in clinical trials. So far, a few small-molecule antiviral drugs (nirmatrelvir-ritonavir, remdesivir and molnupiravir) and 11 monoclonal antibodies have been marketed for the treatment of COVID-19, mostly requiring administration within 10 days of symptom onset. In addition, hospitalized patients with severe or critical COVID-19 may benefit from treatment with previously approved immunomodulatory drugs, including glucocorticoids such as dexamethasone, cytokine antagonists such as tocilizumab and Janus kinase inhibitors such as baricitinib. Here, we summarize progress with COVID-19 drug discovery, based on accumulated findings since the pandemic began and a comprehensive list of clinical and preclinical inhibitors with anti-coronavirus activities. We also discuss the lessons learned from COVID-19 and other infectious diseases with regard to drug repurposing strategies, pan-coronavirus drug targets, in vitro assays and animal models, and platform trial design for the development of therapeutics to tackle COVID-19, long COVID and pathogenic coronaviruses in future outbreaks.
MeSH term(s)	Animals ; Humans ; COVID-19 ; SARS-CoV-2 ; Post-Acute COVID-19 Syndrome ; Antiviral Agents/therapeutic use ; Antiviral Agents/pharmacology
Chemical Substances	Antiviral Agents
Language	English
Publishing date	2023-04-19
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2062954-0
ISSN	1474-1784 ; 1474-1776
ISSN (online)	1474-1784
ISSN	1474-1776
DOI	10.1038/s41573-023-00672-y
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Article ; Online: From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design.

Hilgenfeld, Rolf

The FEBS journal

2014 Volume 281, Issue 18, Page(s) 4085–4096

Abstract: This review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (M(pro) ) and the papain-like ... ...

Abstract	This review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (M(pro) ) and the papain-like protease (PL(pro) ). The role of X-ray crystallography in structure-assisted drug discovery against these targets is discussed. Aspects dealt with in this review include the emergence of the SARS coronavirus in 2002-2003 and of the MERS coronavirus 10 years later and the origins of these viruses. The crystal structure of the free SARS coronavirus M(pro) and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures. The mechanism of maturation of the enzyme from the viral polyprotein is still a matter of debate. The crystal structure of the SARS coronavirus PL(pro) and its complex with ubiquitin is also discussed, as is its orthologue from MERS coronavirus. Efforts at predictive structure-based inhibitor development for bat coronavirus M(pro) s to increase the preparedness against zoonotic transmission to man are described as well. The paper closes with a brief discussion of structure-based discovery of antivirals in an academic setting.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Crystallography, X-Ray ; Drug Design ; Humans ; Models, Molecular ; Molecular Targeted Therapy ; Peptide Hydrolases/chemistry ; Protease Inhibitors/chemistry ; SARS Virus/enzymology ; Viral Proteins/chemistry
Chemical Substances	Antiviral Agents ; Protease Inhibitors ; Viral Proteins ; Peptide Hydrolases (EC 3.4.-)
Keywords	covid19
Language	English
Publishing date	2014-08-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.12936
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Article: Why is the Omicron main protease of SARS-CoV-2 less stable than its wild-type counterpart? A crystallographic, biophysical, and theoretical study of the free enzyme and its complex with inhibitor 13b-K.

Ibrahim, Mohamed / Sun, Xinyuanyuan / de Oliveira, Vinicius Martins / Liu, Ruibin / Clayton, Joseph / Kilani, Haifa El / Shen, Jana / Hilgenfeld, Rolf

bioRxiv : the preprint server for biology

2024

Abstract: During the continuing evolution of SARS-CoV-2, the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November that year. Along with its sublineages, it has maintained a prominent role ever since. The Nsp5 main ... ...

Abstract	During the continuing evolution of SARS-CoV-2, the Omicron variant of concern emerged in the second half of 2021 and has been dominant since November that year. Along with its sublineages, it has maintained a prominent role ever since. The Nsp5 main protease (M
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.04.583178
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Article: H172Y mutation perturbs the S1 pocket and nirmatrelvir binding of SARS-CoV-2 main protease through a nonnative hydrogen bond.

de Oliveira, Vinicius Martins / Ibrahim, Mohamed Fourad / Sun, Xinyuanyuan / Hilgenfeld, Rolf / Shen, Jana

Research square

2022

Abstract: Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro) and the main ingredient of PAXLOVID, a drug approved by FDA for high-risk COVID-19 patients. Although the prevalent Mpro mutants in the SARS-CoV-2 Variants of Concern (e.g., ...

Abstract	Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro) and the main ingredient of PAXLOVID, a drug approved by FDA for high-risk COVID-19 patients. Although the prevalent Mpro mutants in the SARS-CoV-2 Variants of Concern (e.g., Omicron) are still susceptible to nirmatrelvir, a rare natural mutation, H172Y, was found to significantly reduce nirmatrelvir's inhibitory activity. As the selective pressure of antiviral therapy may favor resistance mutations, there is an urgent need to understand the effect of the H172Y mutation on Mpro's structure, function, and drug resistance. Here we report the molecular dynamics (MD) simulations as well as the measurements of stability, enzyme kinetics of H172Y Mpro, and IC
Language	English
Publishing date	2022-08-09
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-1915291/v1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Structure-based antivirals for emerging and neglected RNA viruses: an emerging field for medicinal chemistry in academia.

Hilgenfeld, Rolf

Future medicinal chemistry

2010 Volume 2, Issue 7, Page(s) 1061–1067

Abstract: Many [neglected viruses] predominantly hit developing countries in tropical and subtropical regions of the world (40% of the world's population are now at risk of contracting dengue fever), but developed countries are by no means immune to their impact." ...

Abstract	"Many [neglected viruses] predominantly hit developing countries in tropical and subtropical regions of the world (40% of the world's population are now at risk of contracting dengue fever), but developed countries are by no means immune to their impact."
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Chemistry, Pharmaceutical/trends ; Clinical Trials as Topic ; Developed Countries ; Developing Countries ; Drug Design ; Humans ; Isoxazoles/chemistry ; Isoxazoles/pharmacology ; Isoxazoles/therapeutic use ; Protease Inhibitors/chemistry ; Protease Inhibitors/pharmacology ; Protease Inhibitors/therapeutic use ; Pyrrolidinones/chemistry ; Pyrrolidinones/pharmacology ; Pyrrolidinones/therapeutic use ; RNA Virus Infections/drug therapy ; RNA Viruses/drug effects ; RNA Viruses/enzymology
Chemical Substances	Antiviral Agents ; Isoxazoles ; Protease Inhibitors ; Pyrrolidinones ; rupintrivir (RGE5K1Q5QW)
Language	English
Publishing date	2010-07
Publishing country	England
Document type	Journal Article ; Comment
ISSN	1756-8927
ISSN (online)	1756-8927
DOI	10.4155/fmc.10.211
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Article: From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

Hilgenfeld, Rolf

FEBS journal. 2014 Sept., v. 281, no. 18

2014

Abstract	This review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (Mpro) and the papain‐like protease (PLpro). The role of X‐ray crystallography in structure‐assisted drug discovery against these targets is discussed. Aspects dealt with in this review include the emergence of the SARS coronavirus in 2002–2003 and of the MERS coronavirus 10 years later and the origins of these viruses. The crystal structure of the free SARS coronavirus Mpro and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures. The mechanism of maturation of the enzyme from the viral polyprotein is still a matter of debate. The crystal structure of the SARS coronavirus PLpro and its complex with ubiquitin is also discussed, as is its orthologue from MERS coronavirus. Efforts at predictive structure‐based inhibitor development for bat coronavirus Mpros to increase the preparedness against zoonotic transmission to man are described as well. The paper closes with a brief discussion of structure‐based discovery of antivirals in an academic setting.
Keywords	Chiroptera ; Severe acute respiratory syndrome coronavirus ; X-ray diffraction ; antiviral agents ; crystal structure ; crystallography ; drugs ; pH ; proteinases ; ubiquitin ; viruses ; covid19
Language	English
Dates of publication	2014-09
Size	p. 4085-4096.
Publishing place	Blackwell
Document type	Article
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.12936
Database	NAL-Catalogue (AGRICOLA)

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Article: An Integrative Approach to Dissect the Drug Resistance Mechanism of the H172Y Mutation of SARS-CoV-2 Main Protease.

Clayton, Joseph / de Oliveira, Vinicius Martins / Ibraham, Mohamed Fouad / Sun, Xinyuanyuan / Mahinthichaichan, Paween / Shen, Mingzhe / Hilgenfeld, Rolf / Shen, Jana

bioRxiv : the preprint server for biology

2023

Abstract: Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro) and the main ingredient of PAXLOVID, a drug approved by FDA for high-risk COVID-19 patients. Recently, a rare natural mutation, H172Y, was found to significantly reduce ... ...

Abstract	Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro) and the main ingredient of PAXLOVID, a drug approved by FDA for high-risk COVID-19 patients. Recently, a rare natural mutation, H172Y, was found to significantly reduce nirmatrelvir's inhibitory activity. As the COVID-19 cases skyrocket in China and the selective pressure of antiviral therapy builds up in the US, there is an urgent need to characterize and understand how the H172Y mutation confers drug resistance. Here we investigated the H172Y Mpro's conformational dynamics, folding stability, catalytic efficiency, and inhibitory activity using all-atom constant pH and fixed-charge molecular dynamics simulations, alchemical and empirical free energy calculations, artificial neural networks, and biochemical experiments. Our data suggests that the mutation significantly weakens the S1 pocket interactions with the N-terminus and perturbs the conformation of the oxyanion loop, leading to a decrease in the thermal stability and catalytic efficiency. Importantly, the perturbed S1 pocket dynamics weakens the nirma-trelvir binding in the P1 position, which explains the decreased inhibitory activity of nirmatrelvir. Our work demonstrates the predictive power of the combined simulation and artificial intel-ligence approaches, and together with biochemical experiments they can be used to actively surveil continually emerging mutations of SARS-CoV-2 Mpro and assist the discovery of new antiviral drugs. The presented workflow can be applicable to characterize mutation effects on any protein drug targets.
Language	English
Publishing date	2023-03-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2022.07.31.502215
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Integrative Approach to Dissect the Drug Resistance Mechanism of the H172Y Mutation of SARS-CoV-2 Main Protease.

Clayton, Joseph / de Oliveira, Vinícius Martins / Ibrahim, Mohamed Fouad / Sun, Xinyuanyuan / Mahinthichaichan, Paween / Shen, Mingzhe / Hilgenfeld, Rolf / Shen, Jana

Journal of chemical information and modeling

2023 Volume 63, Issue 11, Page(s) 3521–3533

Abstract: Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro) and the main ingredient of Paxlovid, a drug approved by the U.S. Food and Drug Administration for high-risk COVID-19 patients. Recently, a rare natural mutation, H172Y, was ... ...

Abstract	Nirmatrelvir is an orally available inhibitor of SARS-CoV-2 main protease (Mpro) and the main ingredient of Paxlovid, a drug approved by the U.S. Food and Drug Administration for high-risk COVID-19 patients. Recently, a rare natural mutation, H172Y, was found to significantly reduce nirmatrelvir's inhibitory activity. As the COVID-19 cases skyrocket in China and the selective pressure of antiviral therapy builds in the US, there is an urgent need to characterize and understand how the H172Y mutation confers drug resistance. Here, we investigated the H172Y Mpro's conformational dynamics, folding stability, catalytic efficiency, and inhibitory activity using all-atom constant pH and fixed-charge molecular dynamics simulations, alchemical and empirical free energy calculations, artificial neural networks, and biochemical experiments. Our data suggest that the mutation significantly weakens the S1 pocket interactions with the N-terminus and perturbs the conformation of the oxyanion loop, leading to a decrease in the thermal stability and catalytic efficiency. Importantly, the perturbed S1 pocket dynamics weaken the nirmatrelvir binding in the P1 position, which explains the decreased inhibitory activity of nirmatrelvir. Our work demonstrates the predictive power of the combined simulation and artificial intelligence approaches, and together with biochemical experiments, they can be used to actively surveil continually emerging mutations of SARS-CoV-2 Mpro and assist the optimization of antiviral drugs. The presented approach, in general, can be applied to characterize mutation effects on any protein drug targets.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2/genetics ; SARS-CoV-2/metabolism ; Artificial Intelligence ; Protease Inhibitors/chemistry ; Antiviral Agents/chemistry ; Molecular Dynamics Simulation ; Mutation ; Drug Resistance ; Molecular Docking Simulation
Chemical Substances	nirmatrelvir and ritonavir drug combination ; 3C-like proteinase, SARS-CoV-2 (EC 3.4.22.-) ; Protease Inhibitors ; Antiviral Agents
Language	English
Publishing date	2023-05-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	190019-5
ISSN	1549-960X ; 0095-2338
ISSN (online)	1549-960X
ISSN	0095-2338
DOI	10.1021/acs.jcim.3c00344
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