Proteases of Human Rhinovirus: Role in Infection

Jensen, Lora M.; Walker, Erin J.; Jans, David A.; Ghildyal, Reena

doi:10.1007/978-1-4939-1571-2_10

Cited by 31 publications

(23 citation statements)

References 76 publications

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“…Many bacterial proteases like thermolysin, pseudolysin and auerolysin are virulent factors and hence putative drug targets [ 5 – 8 , 55 ]. However, it is important that drugs targeting the bacterial enzymes not interfere with the function of the human MPs.…”

Section: Introductionmentioning

confidence: 99%

The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases

et al. 2018

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Inhibitors targeting bacterial enzymes should not interfere with enzymes of the host, and knowledge about structural determinants for selectivity is important for designing inhibitors with a therapeutic potential. We have determined the binding strengths of two hydroxamate compounds, galardin and compound 1b for the bacterial zinc metalloproteases, thermolysin, pseudolysin and auerolysin, known to be bacterial virulence factors, and the two human zinc metalloproteases MMP-9 and MMP-14. The active sites of the bacterial and human enzymes have huge similarities. In addition, we also studied the enzyme-inhibitor interactions by molecular modelling. The obtained Ki values of galardin for MMP-9 and MMP-14 and compound 1b for MMP-9 are approximately ten times lower than previously reported. Compound 1b binds stronger than galardin to both MMP-9 and MMP-14, and docking studies indicated that the diphenyl ether moiety of compound 1b obtains more favourable interactions within the S´1-subpocket than the 4-methylpentanoyl moiety of galardin. Both compounds bind stronger to MMP-9 than to MMP-14, which appears to be due to a larger S´1-subpocket in the former enzyme. Galardin, but not 1b, inhibits the bacterial enzymes, but the galardin Ki values were much larger than for the MMPs. The docking indicates that the S´1-subpockets of the bacterial proteases are too small to accommodate the diphenyl ether moiety of 1b, while the 4-methylpentanoyl moiety of galardin enters the pocket. The present study indicates that the size and shape of the ligand structural moiety entering the S´1-subpocket is an important determinant for selectivity between the studied MMPs and bacterial MPs.

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Section: Introductionmentioning

confidence: 99%

The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases

et al. 2018

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“…Viruses have evolved varied strategies to interfere with immune responses of the host, including production of secreted molecules that mimic innate immune receptors, molecules that trap cytokines as well as the shut-off of the cellular transcription and translation machinery [1, 2]. Vaccinia virus (VACV), the virus used to eradicate smallpox, has been extensively studied as a model of virus-host interaction because of its plethora of anti-immune strategies and its large arsenal of immunomodulator tools [3].…”

Section: Introductionmentioning

confidence: 99%

Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins

et al. 2016

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Vaccinia virus interferes with early events of the activation pathway of the transcriptional factor NF-kB by binding to numerous host TIR-domain containing adaptor proteins. We have previously determined the X-ray structure of the A46 C-terminal domain; however, the structure and function of the A46 N-terminal domain and its relationship to the C-terminal domain have remained unclear. Here, we biophysically characterize residues 1–83 of the N-terminal domain of A46 and present the X-ray structure at 1.55 Å. Crystallographic phases were obtained by a recently developed ab initio method entitled ARCIMBOLDO_BORGES that employs tertiary structure libraries extracted from the Protein Data Bank; data analysis revealed an all β-sheet structure. This is the first such structure solved by this method which should be applicable to any protein composed entirely of β-sheets. The A46(1–83) structure itself is a β-sandwich containing a co-purified molecule of myristic acid inside a hydrophobic pocket and represents a previously unknown lipid-binding fold. Mass spectrometry analysis confirmed the presence of long-chain fatty acids in both N-terminal and full-length A46; mutation of the hydrophobic pocket reduced the lipid content. Using a combination of high resolution X-ray structures of the N- and C-terminal domains and SAXS analysis of full-length protein A46(1–240), we present here a structural model of A46 in a tetrameric assembly. Integrating affinity measurements and structural data, we propose how A46 simultaneously interferes with several TIR-domain containing proteins to inhibit NF-κB activation and postulate that A46 employs a bipartite binding arrangement to sequester the host immune adaptors TRAM and MyD88.

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“…Following virus attachment, the genomic RNA of enterovirus is released into the cytoplasm of host cells and translated into a single polyprotein (8). This polyprotein then undergoes viral protease-mediated self-cleavage, first by 2A pro (2A) and then by 3C pro (3C), to generate functional structural and nonstructural viral proteins for subsequent virus genome synthesis and encapsidation (8,9). Besides viral proteins, the substrates of 2A and 3C also encompass many host proteins, such as MAP4 (microtubule-associated protein 4), eIF4G (eukaryotic translation initiation factor 4G), PABP (poly-A-binding protein), RIG-I (retinoic acid-inducible gene I), MAVS (mitochondrial antiviral-signaling protein) and TRIF (TIR-domain-containing adapter-inducing interferon-β) (10,11).…”

mentioning

confidence: 99%

Inhibitory antibodies identify unique sites of therapeutic vulnerability in rhinovirus and other enteroviruses

Meng

Lan

Xie

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The existence of multiple serotypes renders vaccine development challenging for most viruses in theEnterovirusgenus. An alternative and potentially more viable strategy for control of these viruses is to develop broad-spectrum antivirals by targeting highly conserved proteins that are indispensable for the virus life cycle, such as the 3C protease. Previously, two single-chain antibody fragments, YDF and GGVV, were reported to effectively inhibit human rhinovirus 14 proliferation. Here, we found that both single-chain antibody fragments target sites on the 3C protease that are distinct from its known drug site (peptidase active site) and possess different mechanisms of inhibition. YDF does not block the active site but instead noncompetitively inhibits 3C peptidase activity through an allosteric effect that is rarely seen for antibody protease inhibitors. Meanwhile, GGVV antagonizes the less-explored regulatory function of 3C in genome replication. The interaction between 3C and the viral genome 5′ noncoding region has been reported to be important for enterovirus genome replication. Here, the interface between human rhinovirus 14 3C and its 5′ noncoding region was probed by hydrogen–deuterium exchange coupled mass spectrometry and found to partially overlap with the interface between GGVV and 3C. Consistently, prebinding of GGVV completely abolishes interaction between human rhinovirus 14 3C and its 5′ noncoding region. The epitopes of YDF and GGVV, therefore, represent two additional sites of therapeutic vulnerability in rhinovirus. Importantly, the GGVV epitope appears to be conserved across many enteroviruses, suggesting that it is a promising target for pan-enterovirus inhibitor screening and design.

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Proteases of Human Rhinovirus: Role in Infection

Cited by 31 publications

References 76 publications

The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases

The selectivity of galardin and an azasugar-based hydroxamate compound for human matrix metalloproteases and bacterial metalloproteases

Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins

Inhibitory antibodies identify unique sites of therapeutic vulnerability in rhinovirus and other enteroviruses

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