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Article ; Online: Decreased vaccine protection of egg-based influenza vaccine in the elderly and nonhemagglutinin-focused immunity.

Gonzalez, Karen J / Strauch, Eva M

2021 Volume 131, Issue 15

Abstract: Severe influenza illness or death is a serious concern among the elderly population despite vaccination. To investigate how the adaptive immune response after vaccination varies with the patient's age, Jung et al., in a recent issue of the JCI, ... ...

Abstract	Severe influenza illness or death is a serious concern among the elderly population despite vaccination. To investigate how the adaptive immune response after vaccination varies with the patient's age, Jung et al., in a recent issue of the JCI, extensively analyzed the serum antibody response in different age groups after immunization with the egg-based influenza vaccine Fluzone. As expected, the immune response in young adults was dominated by antibodies targeting the influenza hemagglutinin (HA) protein. On the contrary, the serological repertoire of elderly donors was characterized by cross-reactive (CR) antibodies recognizing non-HA antigens. Surprisingly, a substantial fraction of these CR antibodies targeted sulfated glycans typical of egg-produced proteins, which does not provide protection against human influenza viruses. Overall, these findings are of great value in understanding suboptimal immunity after influenza vaccination and shaping future vaccine efforts that will achieve increased protection in the elderly.
MeSH term(s)	Aged ; Antibodies, Viral ; Hemagglutinin Glycoproteins, Influenza Virus ; Humans ; Influenza Vaccines ; Influenza, Human/prevention & control ; Orthomyxoviridae Infections ; Vaccination ; Young Adult
Chemical Substances	Antibodies, Viral ; Hemagglutinin Glycoproteins, Influenza Virus ; Influenza Vaccines
Language	English
Publishing date	2021-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI151732
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Systematic computer-aided disulfide design as a general strategy to stabilize prefusion class I fusion proteins.

Gonzalez, Karen J / Yim, Kevin / Blanco, Jorge Carlos / Boukhvalova, Marina S / Strauch, Eva-Maria

bioRxiv : the preprint server for biology

2024

Abstract: Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing ... ...

Abstract	Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricated task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric constraints of disulfide bonds and introduces a ranking system to estimate their potential in stabilizing the prefusion conformation. We found, for the RSV F protein, that disulfides restricting the initial stages of the conformational switch can offer higher stability to the prefusion state than those preventing unfolding at a later stage. The implementation of our algorithm on the RSV F protein led to the discovery of prefusion-stabilizing disulfides, providing evidence that supports our hypothesis. Furthermore, the evaluation of our top design as a vaccine candidate in a cotton rat model demonstrated robust protection against RSV infection, highlighting the potential of our approach for vaccine development.
Language	English
Publishing date	2024-03-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.29.582784
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting Viral Surface Proteins through Structure-Based Design.

Narkhede, Yogesh B / Gonzalez, Karen J / Strauch, Eva-Maria

Viruses

2021 Volume 13, Issue 7

Abstract: The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the ... ...

Abstract	The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.
MeSH term(s)	Animals ; Antiviral Agents ; Clinical Trials as Topic ; Computer Simulation ; Humans ; Mice ; Respiratory Tract Infections/virology ; Vaccinology/methods ; Viral Envelope Proteins/analysis ; Viral Envelope Proteins/chemistry ; Viral Matrix Proteins/analysis ; Viral Matrix Proteins/chemistry ; Viral Vaccines/analysis ; Viruses/chemistry ; Viruses/classification
Chemical Substances	Antiviral Agents ; Viral Envelope Proteins ; Viral Matrix Proteins ; Viral Vaccines
Language	English
Publishing date	2021-07-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v13071320
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A general computational design strategy for stabilizing viral class I fusion proteins.

Gonzalez, Karen J / Huang, Jiachen / Criado, Miria F / Banerjee, Avik / Tompkins, Stephen M / Mousa, Jarrod J / Strauch, Eva-Maria

Nature communications

2024 Volume 15, Issue 1, Page(s) 1335

Abstract: Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an ... ...

Abstract	Many pathogenic viruses rely on class I fusion proteins to fuse their viral membrane with the host cell membrane. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more stable postfusion state. Mounting evidence underscores that antibodies targeting the prefusion conformation are the most potent, making it a compelling vaccine candidate. Here, we establish a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. With this protocol, we stabilize the fusion proteins of the RSV, hMPV, and SARS-CoV-2 viruses, testing fewer than a handful of designs. The solved structures of these designed proteins from all three viruses evidence the atomic accuracy of our approach. Furthermore, the humoral response of the redesigned RSV F protein compares to that of the recently approved vaccine in a mouse model. While the parallel design of two conformations allows the identification of energetically sub-optimal positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.
MeSH term(s)	Animals ; Mice ; Viral Fusion Proteins ; Antibodies, Neutralizing ; Antibodies, Viral ; Vaccines ; Protein Conformation
Chemical Substances	Viral Fusion Proteins ; Antibodies, Neutralizing ; Antibodies, Viral ; Vaccines
Language	English
Publishing date	2024-02-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45480-z
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: A general computational design strategy for stabilizing viral class I fusion proteins.

Gonzalez, Karen J / Huang, Jiachen / Criado, Miria F / Banerjee, Avik / Tompkins, Stephen / Mousa, Jarrod J / Strauch, Eva-Maria

bioRxiv : the preprint server for biology

2023

Abstract: Many pathogenic viruses, including influenza virus, Ebola virus, coronaviruses, and Pneumoviruses, rely on class I fusion proteins to fuse viral and cellular membranes. To drive the fusion process, class I fusion proteins undergo an irreversible ... ...

Abstract	Many pathogenic viruses, including influenza virus, Ebola virus, coronaviruses, and Pneumoviruses, rely on class I fusion proteins to fuse viral and cellular membranes. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more favorable and stable postfusion state. An increasing amount of evidence exists highlighting that antibodies targeting the prefusion conformation are the most potent. However, many mutations have to be evaluated before identifying prefusion-stabilizing substitutions. We therefore established a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. As a proof of concept, we applied this principle to the fusion protein of the RSV, hMPV, and SARS-CoV-2 viruses. For each protein, we tested less than a handful of designs to identify stable versions. Solved structures of designed proteins from the three different viruses evidenced the atomic accuracy of our approach. Furthermore, the immunological response of the RSV F design compared to a current clinical candidate in a mouse model. While the parallel design of two conformations allows identifying and selectively modifying energetically less optimized positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. We recaptured many approaches previously introduced manually for the stabilization of viral surface proteins, such as cavity-filling, optimization of polar interactions, as well as postfusion-disruptive strategies. Using our approach, it is possible to focus on the most impacting mutations and potentially preserve the immunogen as closely as possible to its native version. The latter is important as sequence re-design can cause perturbations to B and T cell epitopes. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.
Language	English
Publishing date	2023-03-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.16.532924
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Targeting Viral Surface Proteins through Structure-Based Design

Narkhede, Yogesh B / Gonzalez, Karen J / Strauch, Eva-Maria

Viruses. 2021 July 08, v. 13, no. 7

2021

Abstract	The emergence of novel viral infections of zoonotic origin and mutations of existing human pathogenic viruses represent a serious concern for public health. It warrants the establishment of better interventions and protective therapies to combat the virus and prevent its spread. Surface glycoproteins catalyzing the fusion of viral particles and host cells have proven to be an excellent target for antivirals as well as vaccines. This review focuses on recent advances for computational structure-based design of antivirals and vaccines targeting viral fusion machinery to control seasonal and emerging respiratory viruses.
Keywords	antiviral agents ; glycoproteins ; pathogens ; public health ; viruses
Language	English
Dates of publication	2021-0708
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2516098-9
ISSN	1999-4915
ISSN	1999-4915
DOI	10.3390/v13071320
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: In silico identification of potential inhibitors against human 2'-5'- oligoadenylate synthetase (OAS) proteins.

Gonzalez, Karen J / Moncada-Giraldo, Diego M / Gutierrez, Juan B

Computational biology and chemistry

2020 Volume 85, Page(s) 107211

Abstract: As part of the type I IFN signaling, the 2'-5'- oligoadenylate synthetase (OAS) proteins have been involved in the progression of several non-viral diseases. Notably, OAS has been correlated with immune-modulatory functions that promote chronic ... ...

Abstract	As part of the type I IFN signaling, the 2'-5'- oligoadenylate synthetase (OAS) proteins have been involved in the progression of several non-viral diseases. Notably, OAS has been correlated with immune-modulatory functions that promote chronic inflammatory conditions, autoimmune disorders, cancer, and infectious diseases. In spite of this, OAS enzymes have been ignored as drug targets, and to date, there are no reports of compounds that can inhibit their activity. In this study, we have used homology modeling and virtual high-throughput screening to identify potential inhibitors of the human proteins OAS1, OAS2, and OAS3. Altogether, we have found 37 molecules that could exert a competitive inhibition in the ATP binding sites of OAS proteins, independently of the activation state of the enzyme. This latter characteristic, which might be crucial for a versatile inhibitor, was observed in compounds interacting with the residues Asp75, Asp77, Gln229, and Tyr230 in OAS1, and their equivalents in OAS2 and OAS3. Although there was little correlation between specific chemical fragments and their interactions, intermolecular contacts with OAS catalytic triad and other critical amino acids were mainly promoted by heterocycles with π electrons and hydrogen bond acceptors. In conclusion, this study provides a potential set of OAS inhibitors as well as valuable information for their design, development, and optimization.
MeSH term(s)	2',5'-Oligoadenylate Synthetase/antagonists & inhibitors ; 2',5'-Oligoadenylate Synthetase/metabolism ; Computational Biology ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; High-Throughput Screening Assays ; Humans ; Models, Molecular
Chemical Substances	Enzyme Inhibitors ; OAS1 protein, human (EC 2.7.7.-) ; OAS2 protein, human (EC 2.7.7.-) ; 2',5'-Oligoadenylate Synthetase (EC 2.7.7.84) ; OAS3 protein, human (EC 2.7.7.84)
Language	English
Publishing date	2020-01-22
Publishing country	England
Document type	Journal Article
ISSN	1476-928X
ISSN (online)	1476-928X
DOI	10.1016/j.compbiolchem.2020.107211
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A general computational design strategy for stabilizing viral class I fusion proteins

Gonzalez, Karen J / Huang, Jiachen / Criado, Miria F / Banerjee, Avik / Tompkins, Stephen Mark / Mousa, Jarrod J / Strauch, Eva Maria

bioRxiv

Abstract	Many pathogenic viruses, including influenza virus, Ebola virus, coronaviruses, and Pneumoviruses, rely on class I fusion proteins to fuse viral and cellular membranes. To drive the fusion process, class I fusion proteins undergo an irreversible conformational change from a metastable prefusion state to an energetically more favorable and stable postfusion state. An increasing amount of evidence exists highlighting that antibodies targeting the prefusion conformation are the most potent. However, many mutations have to be evaluated before identifying prefusion-stabilizing substitutions. We therefore established a computational design protocol that stabilizes the prefusion state while destabilizing the postfusion conformation. As a proof of concept, we applied this principle to the fusion protein of the RSV, hMPV, and SARS-CoV-2 viruses. For each protein, we tested less than a handful of designs to identify stable versions. Solved structures of designed proteins from the three different viruses evidenced the atomic accuracy of our approach. Furthermore, the immunological response of the RSV F design compared to a current clinical candidate in a mouse model. While the parallel design of two conformations allows identifying and selectively modifying energetically less optimized positions for one conformation, our protocol also reveals diverse molecular strategies for stabilization. We recaptured many approaches previously introduced manually for the stabilization of viral surface proteins, such as cavity-filling, optimization of polar interactions, as well as postfusion-disruptive strategies. Using our approach, it is possible to focus on the most impacting mutations and potentially preserve the immunogen as closely as possible to its native version. The latter is important as sequence re-design can cause perturbations to B and T cell epitopes. Given the clinical significance of viruses using class I fusion proteins, our algorithm can substantially contribute to vaccine development by reducing the time and resources needed to optimize these immunogens.
Keywords	covid19
Language	English
Publishing date	2023-03-17
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.03.16.532924
Database	COVID19

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Article ; Online: Skp1 Dimerization Conceals Its F-Box Protein Binding Site.

Kim, Hyun W / Eletsky, Alexander / Gonzalez, Karen J / van der Wel, Hanke / Strauch, Eva-Maria / Prestegard, James H / West, Christopher M

Biochemistry

2020 Volume 59, Issue 15, Page(s) 1527–1536

Abstract: Skp1 is an adapter that links F-box proteins to cullin-1 in the Skp1/cullin-1/F-box (SCF) protein family of E3 ubiquitin ligases that targets specific proteins for polyubiquitination and subsequent protein degradation. Skp1 from the ... ...

Abstract	Skp1 is an adapter that links F-box proteins to cullin-1 in the Skp1/cullin-1/F-box (SCF) protein family of E3 ubiquitin ligases that targets specific proteins for polyubiquitination and subsequent protein degradation. Skp1 from the amoebozoan
MeSH term(s)	Binding Sites ; Dimerization ; F-Box Proteins/chemistry ; F-Box Proteins/metabolism ; Humans ; Models, Molecular ; S-Phase Kinase-Associated Proteins/chemistry ; S-Phase Kinase-Associated Proteins/metabolism
Chemical Substances	F-Box Proteins ; S-Phase Kinase-Associated Proteins ; SKP1 protein, human
Language	English
Publishing date	2020-04-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.0c00094
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 217: Show issues

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Article: Skp1 Dimerization Conceals Its F-Box Protein Binding Site

Kim, Hyun W / Eletsky, Alexander / Gonzalez, Karen J / van der Wel, Hanke / Strauch, Eva-Maria / Prestegard, James H / West, Christopher M

Biochemistry. 2020 Mar. 30, v. 59, no. 15

2020

Abstract	Skp1 is an adapter that links F-box proteins to cullin-1 in the Skp1/cullin-1/F-box (SCF) protein family of E3 ubiquitin ligases that targets specific proteins for polyubiquitination and subsequent protein degradation. Skp1 from the amoebozoan Dictyostelium forms a stable homodimer in vitro with a Kd of 2.5 μM as determined by sedimentation velocity studies yet is monomeric in crystal complexes with F-box proteins. To investigate the molecular basis for the difference, we determined the solution NMR structure of a doubly truncated Skp1 homodimer (Skp1ΔΔ). The solution structure of the Skp1ΔΔ dimer reveals a 2-fold symmetry with an interface that buries ∼750 Å² of predominantly hydrophobic surface. The dimer interface overlaps with subsite 1 of the F-box interaction area, explaining why only the Skp1 monomer binds F-box proteins (FBPs). To confirm the model, Rosetta was used to predict amino acid substitutions that might disrupt the dimer interface, and the F97E substitution was chosen to potentially minimize interference with F-box interactions. A nearly full-length version of Skp1 with this substitution (Skp1ΔF97E) behaved as a stable monomer at concentrations of ≤500 μM and actively bound a model FBP, mammalian Fbs1, which suggests that the dimeric state is not required for Skp1 to carry out a basic biochemical function. Finally, Skp1ΔF97E is expected to serve as a monomer model for high-resolution NMR studies previously hindered by dimerization.
Keywords	Dictyostelium ; F-box proteins ; amino acid substitution ; area ; binding sites ; dimerization ; hydrophobicity ; mammals ; models ; protein degradation ; ubiquitin-protein ligase ; ubiquitination ; velocity
Language	English
Dates of publication	2020-0330
Size	p. 1527-1536.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-light
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.0c00094
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 217: Show issues

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ab Jg. 2022: Lesesaal (EG)

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