Dataset Information

Controlled Protein Activities with Viral Proteases, Antiviral Peptides, and Antiviral Drugs.

ABSTRACT: Chemical control of protein activity is a powerful tool for scientific study, synthetic biology, and cell therapy; however, for broad use, effective chemical inducer systems must minimally crosstalk with endogenous processes and exhibit desirable drug delivery properties. Accordingly, the drug-controllable proteolytic activity of hepatitis C cis-protease NS3 and its associated antiviral drugs have been used to regulate protein activity and gene modulation. These tools advantageously exploit non-eukaryotic and non-prokaryotic proteins and clinically approved inhibitors. Here, we expand the toolkit by utilizing catalytically inactive NS3 protease as a high affinity binder to genetically encoded, antiviral peptides. Through our approach, we create NS3-peptide complexes that can be displaced by FDA-approved drugs to modulate transcription, cell signaling, and split-protein complementation. With our developed system, we invented a new mechanism to allosterically regulate Cre recombinase. Allosteric Cre regulation with NS3 ligands enables orthogonal recombination tools in eukaryotic cells and functions in divergent organisms to control prokaryotic recombinase activity.

SUBMITTER: Tague EP

PROVIDER: S-EPMC10501127 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Controlled Protein Activities with Viral Proteases, Antiviral Peptides, and Antiviral Drugs.

Tague Elliot P EP McMahan Jeffrey B JB Tague Nathan N Dunlop Mary J MJ Ngo John T JT

ACS chemical biology 20230504 5

Chemical control of protein activity is a powerful tool for scientific study, synthetic biology, and cell therapy; however, for broad use, effective chemical inducer systems must minimally crosstalk with endogenous processes and exhibit desirable drug delivery properties. Accordingly, the drug-controllable proteolytic activity of hepatitis C <i>cis-</i>protease NS3 and its associated antiviral drugs have been used to regulate protein activity and gene modulation. These tools advantageously explo ...[more]

PMID: 37140437

Similar Datasets

Project description:Background & aimsUnlike other hepatitis viruses that have infected primates for millions of years, hepatitis A virus (HAV) likely entered human populations only 10-12 thousand years ago after jumping from a rodent host. The phylogeny of modern hepatoviruses that infect rodents and bats suggest that multiple similar host shifts have occurred in the past. The factors determining such shifts are unknown, but the capacity to overcome innate antiviral responses in a foreign species is likely key.MethodsWe assessed the capacity of diverse hepatovirus 3ABC proteases to cleave mitochondrial antiviral signaling protein (MAVS) and disrupt antiviral signaling in HEK293 and human hepatocyte-derived cell lines. We also applied maximum-likelihood and Bayesian algorithms to identify sites of diversifying selection in MAVS orthologs from 75 chiropteran, rodent and primate species.Results3ABC proteases from bat, but not rodent hepatoviruses efficiently cleaved human MAVS at Glu463/Gly464, disrupting virus activation of the interferon-β promoter, whereas human HAV 3ABC cleaved at Gln427/Val428. In contrast, MAVS orthologs from rodents and bats were resistant to cleavage by 3ABC proteases of cognate hepatoviruses and in several cases human HAV. A search for diversifying selection among MAVS orthologs from all 3 orders revealed 90 of ∼540 residues to be under positive selection, including residues in chiropteran MAVS that align with the site of cleavage of human MAVS by bat 3ABC proteases.Conclusions3ABC protease cleavage of MAVS is a conserved attribute of hepatoviruses, acting broadly across different mammalian species and associated with evidence of diversifying selection at cleavage sites in rodent and bat MAVS orthologs. The capacity of hepatoviruses to disrupt MAVS-mediated innate immune responses has shaped evolution of both hepatoviruses and their hosts, and facilitates cross-species transmission of hepatitis A.Lay summaryHepatitis A virus, a common cause of acute hepatitis globally, is likely to have evolved from a virus that jumped from a rodent species to humans within the last 10-12 thousand years. Here we show that distantly related hepatoviruses, that infect bats and rodents today, express proteases that disrupt innate antiviral responses in human cells. This conserved attribute of hepatoviruses may have contributed to that ancient host species shift.

Dataset Information

Controlled Protein Activities with Viral Proteases, Antiviral Peptides, and Antiviral Drugs.

Publications

Controlled Protein Activities with Viral Proteases, Antiviral Peptides, and Antiviral Drugs.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets