Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza.
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ABSTRACT:
SUBMITTER: Rahbar Saadat Y
PROVIDER: S-EPMC8435734 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The novel corona virus (SARS-CoV-2) that causes severe acute respiratory syndrome, now called COVID-19 initially originated in Wuhan city of China and later spread across borders and infected more than five million people and killed over 3.4 lakh people all over the globe. This disease has been announced as pandemic by WHO. So far, there has been not much progress in terms of drug development for fighting against this deadliest virus, also no existing drugs has been reported completely effective for COVID-19 treatment owing to lack of effective therapeutic targets and a broad understanding of the viral behavior in target cell. Some reports have found and confirmed that SARS-CoV-2 like others SARS-CoVs utilizes angiotensin converting enzyme-2 receptor for making entry into target cell by binding to the receptor with its S1 subunit and employing host cell proteases for cleaving S2 subunit at S2' in order to fuse with cell membrane. Thus, simultaneous blocking of S1 subunit and inactivation of proteases seem to be promising therapeutic targets for the development of effective novel drugs. In current write up we hypothesize that S1 subunit and host proteases as potential therapeutic avenues for the treatment of COVID-19.
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Project description:Over one third of all known proteolytic enzymes are serine proteases. Among these, the trypsins underwent the most predominant genetic expansion yielding the enzymes responsible for digestion, blood coagulation, fibrinolysis, development, fertilization, apoptosis, and immunity. The success of this expansion resides in a highly efficient fold that couples catalysis and regulatory interactions. Added complexity comes from the recent observation of a significant conformational plasticity of the trypsin fold. A new paradigm emerges where two forms of the protease, E* and E, are in allosteric equilibrium and determine biological activity and specificity.
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Project description:The human HtrA family of serine proteases consists of four members: HtrA1, HtrA2, HtrA3 and HtrA4. Although prokaryotic HtrA proteins are well characterized in their dual roles as chaperones and proteases that degrade misfolded proteins in the periplasm, some members of mammalian HtrA proteins are described as potential modulators of programmed cell death and chemotherapy-induced cytotoxicity. Goal of this review article is to describe the molecular alterations associated with these HtrA serine proteases and how these alterations may be associated with tumor behavior and response to chemotherapy. We will also discuss evidence that chemotherapeutic drugs regulate the expression and activation of HtrA serine proteases and that these proteases contributes to programmed cell death. Finally, we will discuss the potential role of epigenetic therapy in targeting the expression and activation of HtrA serine proteases and the mechanisms by which these proteases enhance cytotoxic effect of conventional chemotherapy.
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Project description:SPINK6 was identified in human skin as a cellular inhibitor of serine proteases of the KLK family. Airway serine proteases are required to cleave hemagglutinin (HA) of influenza A viruses (IAVs) to initiate an infection in the human airway. We hypothesized that SPINK6 may inhibit common airway serine proteases and restrict IAV activation. We demonstrate that SPINK6 specifically suppresses the proteolytic activity of HAT and KLK5, HAT- and KLK5-mediated HA cleavage, and restricts virus maturation and replication. SPINK6 constrains the activation of progeny virions and impairs viral growth; and vice versa, blocking endogenous SPINK6 enhances HA cleavage and viral growth in physiological-relevant human airway organoids where SPINK6 is intrinsically expressed. In IAV-infected mice, SPINK6 significantly suppresses viral growth and improves mouse survival. Notably, individuals carrying the higher SPINK6-expression allele were protected from human H7N9 infection. Collectively, SPINK6 is a novel host inhibitor of serine proteases in the human airway and restricts IAV activation.
| S-SCDT-EMM-2021-14485 | biostudies-other
Project description:Pieris brassicae L. is a serious pest of cultivated crucifers in several parts of the world. Larvae of P. brassicae also feed prolifically on garden nasturtium (Tropaeolum majus L., of the family Tropaeolaceae). Proteolytic digestion was studied in larvae feeding on multiple hosts. Fourth instars were collected from cauliflower fields before transfer onto detached, aerial tissues of selected host plants in the lab. Variable levels of midgut proteases were detected in larvae fed on different hosts using protein substrates (casein and recombinant RBCL cloned from cauliflower) and diagnostic, synthetic substrates. Qualitative changes in midgut trypsin activities and quantitative changes in midgut chymotrypsin activities were implicated in physiological adaptation of larvae transferred to T. majus. Midgut proteolytic activities were inhibited to different extents by serine protease inhibitors, including putative trypsin inhibitors isolated from herbivore-attacked and herbivore-free leaves of cauliflower (CfTI) and T. majus (TpTI). Transfer of larvae to T. majus significantly influenced feeding parameters but not necessarily when transferred to different tissues of the same host. Results obtained are relevant for devising sustainable pest management strategies, including transgenic approaches using genes encoding plant protease inhibitors.
| S-EPMC4379908 | biostudies-literature
Project description:The unprecedented pandemic of coronavirus disease 2019 (COVID-19) demands effective treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The infection of SARS-CoV-2 critically depends on diverse viral or host proteases, which mediate viral entry, viral protein maturation, as well as the pathogenesis of the viral infection. Endogenous and exogenous agents targeting for proteases have been proved to be effective toward a variety of viral infections ranging from HIV to influenza virus, suggesting protease inhibitors as a promising antiviral treatment for COVID-19. In this Review, we discuss how host and viral proteases participated in the pathogenesis of COVID-19 as well as the prospects and ongoing clinical trials of protease inhibitors as treatments.
| S-EPMC7640965 | biostudies-literature
Project description:Immune dysregulation characterized by T cell exhaustion and high level of inflammatory cytokines is associated with severe COVID-19. Figuring out the early event of immune dysregulation would provide a potential treatment for COVID-19. Recent evidence indicate that mitochondrial dysfunction participates in the development of COVID-19 and may be responsible for the dysregulated immune response. Mitochondrial-targeted ubiquinone (MitoQ), a mitochondrial-targeted antioxidant, shows beneficial effects on various diseases through improving mitochondrial dysfunction. We hypothesize that MitoQ could act as a potential treatment in COVID-19. MitoQ may alleviate cytokine storm and restore the function of exhausted T cells in COVID-19 patients through improving mitochondrial dysfunction. In this article, we provide evidence to support the use of MitoQ as a potential treatment or adjunct therapy in the context of COVID-19.
| S-EPMC7403158 | biostudies-literature
Project description:Background: The risk of co-epidemic between COVID-19 and influenza is very high, so it is urgent to find a treatment strategy for the co-infection. Previous studies have shown that phillyrin can not only inhibit the replication of the two viruses, but also has a good anti-inflammatory effect, which is expected to become a candidate compound against COVID-19 and influenza. Objective: To explore the possibility of phillyrin as a candidate compound for the treatment of COVID-19 and influenza co-infection and to speculate its potential regulatory mechanism. Methods: We used a series of bioinformatics network pharmacology methods to understand and characterize the pharmacological targets, biological functions, and therapeutic mechanisms of phillyrin in COVID-19 and influenza co-infection and discover its therapeutic potential. Results: We revealed potential targets, biological processes, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and upstream pathway activity of phillyrin against COVID-19 and influenza co-infection. We constructed protein-protein interaction (PPI) network and identified 50 hub genes, such as MMP9, IL-2, VEGFA, AKT, and HIF-1A. Furthermore, our findings indicated that the treatment of phillyrin for COVID-19 and influenza co-infection was associated with immune balance and regulation of hypoxia-cytokine storm, including HIF-1 signaling pathway, PI3K-Akt signaling pathway, Ras signaling pathway, and T cell receptor signaling pathway. Conclusion: For the first time, we uncovered the potential targets and biological pathways of phillyrin for COVID-19 and influenza co-infection. These findings should solve the urgent problem of co-infection of COVID-19 and influenza that the world will face in the future, but clinical drug trials are needed for verification in the future.
| S-EPMC8599367 | biostudies-literature
Project description:Serine protease inhibitors (serpins) regulate proteolytic events within diverse biological processes, including digestion, coagulation, inflammation and immune responses. The presence of serpins in Fasciola hepatica excretory-secretory products indicates that the parasite exploits these to regulate proteases encountered during its development within vertebrate hosts. Interrogation of the F. hepatica genome identified a multi-gene serpin family of seven members that has expanded by gene duplication and divergence to create an array of inhibitors with distinct specificities. We investigated the molecular properties and functions of two representatives, FhSrp1 and FhSrp2, highly expressed in the invasive newly excysted juvenile (NEJ). Consistent with marked differences in the reactive centre loop (RCL) that executes inhibitor-protease complexing, the two recombinant F. hepatica serpins displayed distinct inhibitory profiles against an array of mammalian serine proteases. In particular, rFhSrp1 efficiently inhibited kallikrein (Ki = 40 nM) whilst rFhSrp2 was a highly potent inhibitor of chymotrypsin (Ki = 0.07 nM). FhSrp1 and FhSrp2 are both expressed on the NEJ surface, predominantly around the oral and ventral suckers, suggesting that these inhibitors protect the parasites from the harmful proteolytic effects of host proteases, such as chymotrypsin, during invasion. Furthermore, the unusual inhibition of kallikrein suggests that rFhSrp1 modulates host responses such as inflammation and vascular permeability by interfering with the kallikrein-kinin system. A vaccine combination of rFhSrp1 and rFhSrp2 formulated in the adjuvant Montanide ISA 206VG elicited modest but non-significant protection against a challenge infection in a rat model, but did induce some protection against liver pathogenesis when compared to a control group and a group vaccinated with two well-studied vaccine candidates, F. hepatica cathepsin L2 and L3. This work highlights the importance of F. hepatica serpins to regulate host responses that enables parasite survival during infection and, coupled with the vaccine data, encourages future vaccine trials in ruminants.
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Project description:Over one third of all known proteolytic enzymes are serine proteases. Among these, the trypsin-like serine proteases comprise one of the best characterized subfamilies due to their essential roles in blood coagulation, food digestion, fibrinolysis, or immunity. Trypsin-like serine proteases possess primary substrate specificity for basic amino acids. Most of the well-characterized trypsin-like proteases such as trypsin, plasmin, or urokinase are soluble proteases that are secreted into the extracellular environment. At the turn of the millennium, a number of novel trypsin-like serine proteases have been identified that are anchored in the cell membrane, either by a transmembrane domain at the N- or C-terminus or via a glycosylphosphatidylinositol (GPI) linkage. Meanwhile more than 20 membrane-anchored serine proteases (MASPs) have been identified in human and mouse, and some of them have emerged as key regulators of mammalian development and homeostasis. Thus, the MASP corin and TMPRSS6/matriptase-2 have been demonstrated to be the activators of the atrial natriuretic peptide (ANP) and key regulator of hepcidin expression, respectively. Furthermore, MASPs have been recognized as host cell factors activating respiratory viruses including influenza virus as well as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses. In particular, transmembrane protease serine S1 member 2 (TMPRSS2) has been shown to be essential for proteolytic activation and consequently spread and pathogenesis of a number of influenza A viruses in mice and as a factor associated with severe influenza virus infection in humans. This review gives an overview on the physiological functions of the fascinating and rapidly evolving group of MASPs and a summary of the current knowledge on their role in proteolytic activation of viral fusion proteins.
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