About: Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants

Facets (new session)
Description
Metadata
Settings
- owl:sameAs
- Inference Rule:

About: Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants
Creator	Kikkert, Marjolein Zhang, Wei Gu, Jun He, Wenguang Khare, Baldeep Bailey-Elkin, Ben Dalebout, Tim Johnson, Garrett Knaap, Mark, Brian Mcleish, Nigel Sidhu, Sachdev Van Kasteren, Puck
Source	Medline; PMC
abstract	The recent Middle East respiratory syndrome coronavirus (MERS-CoV), Ebola and Zika virus outbreaks exemplify the continued threat of (re-)emerging viruses to human health, and our inability to rapidly develop effective therapeutic countermeasures. Many viruses, including MERS-CoV and the Crimean-Congo hemorrhagic fever virus (CCHFV) encode deubiquitinating (DUB) enzymes that are critical for viral replication and pathogenicity. They bind and remove ubiquitin (Ub) and interferon stimulated gene 15 (ISG15) from cellular proteins to suppress host antiviral innate immune responses. A variety of viral DUBs (vDUBs), including the MERS-CoV papain-like protease, are responsible for cleaving the viral replicase polyproteins during replication, and are thereby critical components of the viral replication cycle. Together, this makes vDUBs highly attractive antiviral drug targets. However, structural similarity between the catalytic cores of vDUBs and human DUBs complicates the development of selective small molecule vDUB inhibitors. We have thus developed an alternative strategy to target the vDUB activity through a rational protein design approach. Here, we report the use of phage-displayed ubiquitin variant (UbV) libraries to rapidly identify potent and highly selective protein-based inhibitors targeting the DUB domains of MERS-CoV and CCHFV. UbVs bound the vDUBs with high affinity and specificity to inhibit deubiquitination, deISGylation and in the case of MERS-CoV also viral replicative polyprotein processing. Co-crystallization studies further revealed critical molecular interactions between UbVs and MERS-CoV or CCHFV vDUBs, accounting for the observed binding specificity and high affinity. Finally, expression of UbVs during MERS-CoV infection reduced infectious progeny titers by more than four orders of magnitude, demonstrating the remarkable potency of UbVs as antiviral agents. Our results thereby establish a strategy to produce protein-based inhibitors that could protect against a diverse range of viruses by providing UbVs via mRNA or protein delivery technologies or through transgenic techniques.
has issue date	2017-05-18(xsd:dateTime)
bibo:doi	10.1371/journal.ppat.1006372
bibo:pmid	28542609
has license	cc-by
sha1sum (hex)	eb4451db661165d4d518ea8b812b9d0963e84736
schema:url	https://doi.org/10.1371/journal.ppat.1006372
resource representing a document's title	Potent and selective inhibition of pathogenic viruses by engineered ubiquitin variants
has PubMed Central identifier	PMC5451084
has PubMed identifier	28542609
schema:publication	PLoS Pathog
resource representing a document's body	covid:eb4451db661165d4d518ea8b812b9d0963e84736#body_text
is schema:about of	named entity 'AUTHOR' named entity 'molecular interactions' named entity 'MERS-CoV' named entity 'structural similarity' named entity 'inhibitors' named entity 'technologies' named entity 'UBIQUITIN' named entity 'TO PRODUCE' named entity 'MOLECULAR INTERACTIONS' named entity 'SUPPRESS' named entity 'THREAT' named entity 'STRATEGY' named entity 'AFFINITY' named entity 'APPROACH' named entity 'HAVE' named entity 'POLYPROTEINS' named entity 'USE OF' named entity 'BOUND' named entity 'EXPRESSION' named entity 'ATTRACTIVE' named entity 'PROTEIN DELIVERY' named entity 'STUDIES' named entity 'TARGETING' named entity 'INHIBITORS' named entity 'TECHNIQUES' named entity 'TECHNOLOGIES' named entity 'HUMAN' named entity 'MRNA' named entity 'ENZYMES' named entity 'RECENT' named entity 'HIGH' named entity 'PAPAIN' named entity 'REPLICATION' named entity 'REPORT' named entity 'IMMUNE RESPONSES' named entity 'PROCESSING' named entity 'RAPIDLY' named entity 'PATHOGENICITY' named entity 'REMOVE' named entity 'ESTABLISH' named entity 'INCLUDING' named entity 'OUR' named entity 'VARIANT' named entity 'PROTEASE' named entity 'VIRAL REPLICATION CYCLE' named entity 'SIMILARITY' named entity 'TRANSGENIC' named entity 'TO INHIBIT' named entity 'REDUCED' named entity 'ANTIVIRAL AGENTS' named entity 'CORES' named entity 'INTERFERON STIMULATED GENE 15' named entity 'ACCOUNTING' named entity 'DRUG TARGETS' named entity 'RANGE' named entity 'CO-CRYSTALLIZATION' named entity 'ZIKA VIRUS' named entity 'RESPONSIBLE' named entity 'THERAPEUTIC' named entity 'VIRUSES' named entity 'PATHOGENIC' named entity 'THE DUB' named entity 'RATIONAL PROTEIN DESIGN' named entity 'VARIETY' named entity 'DEUBIQUITINATING' named entity 'VIRAL REPLICATION' named entity 'DEVELOPMENT' named entity 'LIBRARIES' named entity 'CELLULAR'

Faceted Search & Find service v1.13.91 as of Mar 24 2020

Alternative Linked Data Documents: Sponger | ODE Content Formats:

RDF

ODATA

Microdata

About

OpenLink Virtuoso version 07.20.3229 as of Jul 10 2020, on Linux (x86_64-pc-linux-gnu), Single-Server Edition (94 GB total memory)
Data on this page belongs to its respective rights holders.
Virtuoso Faceted Browser Copyright © 2009-2024 OpenLink Software