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      Brown spider venom toxins: what are the functions of astacins, serine proteases, hyaluronidases, allergens, TCTP, serpins and knottins?

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          Abstract

          Accidents caused by the bites of brown spiders ( Loxosceles) generate a clinical condition that often includes a threatening necrotic skin lesion near the bite site along with a remarkable inflammatory response. Systemic disorders such as hemolysis, thrombocytopenia, and acute renal failure may occur, but are much less frequent than the local damage. It is already known that phospholipases D, highly expressed toxins in Loxosceles venom, can induce most of these injuries. However, this spider venom has a great range of toxins that probably act synergistically to enhance toxicity. The other protein classes remain poorly explored due to the difficulty in obtaining sufficient amounts of them for a thorough investigation. They include astacins (metalloproteases), serine proteases, knottins, translationally controlled tumor proteins (TCTP), hyaluronidases, allergens and serpins. It has already been shown that some of them, according to their characteristics, may participate to some extent in the development of loxoscelism. In addition, all of these toxins present potential application in several areas. The present review article summarizes information regarding some functional aspects of the protein classes listed above, discusses the directions that could be taken to materialize a comprehensive investigation on each of these toxins as well as highlights the importance of exploring the full venom repertoire.

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Protease inhibitors targeting coronavirus and filovirus entry

            Highlights • We identify vinylsulfones as lead candidate inhibitors of Ebola virus and SARS-CoV. • K11777 inhibited Ebola virus and SARS-CoV entry in the sub-nanomolar range. • Potent inhibition correlated with the presence of a basic piperazine ring at P3. • Serine protease inhibitor and K11777 blocked coronavirus entry into caco-2 cells. • Camostat protected 6 out of ten mice from lethal infection with SARS-CoV.
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              The magic glue hyaluronan and its eraser hyaluronidase: a biological overview.

              Hyaluronan (HA) is a multifunctional high molecular weight polysaccharide found throughout the animal kingdom, especially in the extracellular matrix (ECM) of soft connective tissues. HA is thought to participate in many biological processes, and its level is markedly elevated during embryogenesis, cell migration, wound healing, malignant transformation, and tissue turnover. The enzymes that degrade HA, hyaluronidases (HAases) are expressed both in prokaryotes and eukaryotes. These enzymes are known to be involved in physiological and pathological processes ranging from fertilization to aging. Hyaluronidase-mediated degradation of HA increases the permeability of connective tissues and decreases the viscosity of body fluids and is also involved in bacterial pathogenesis, the spread of toxins and venoms, acrosomal reaction/ovum fertilization, and cancer progression. Furthermore, these enzymes may promote direct contact between pathogens and the host cell surfaces. Depolymerization of HA also adversely affects the role of ECM and impairs its activity as a reservoir of growth factors, cytokines and various enzymes involved in signal transduction. Inhibition of HA degradation therefore may be crucial in reducing disease progression and spread of venom/toxins and bacterial pathogens. Hyaluronidase inhibitors are potent, ubiquitous regulating agents that are involved in maintaining the balance between the anabolism and catabolism of HA. Hyaluronidase inhibitors could also serve as contraceptives and anti-tumor agents and possibly have antibacterial and anti-venom/toxin activities. Additionally, these molecules can be used as pharmacological tools to study the physiological and pathophysiological role of HA and hyaluronidases.
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                Author and article information

                Journal
                J Venom Anim Toxins Incl Trop Dis
                J Venom Anim Toxins Incl Trop Dis
                jvatitd
                The Journal of Venomous Animals and Toxins Including Tropical Diseases
                Centro de Estudos de Venenos e Animais Peçonhentos
                1678-9199
                12 July 2021
                2021
                : 27
                : e20200188
                Affiliations
                [1 ]Department of Cell Biology, Federal University of Paraná (UFPR), Curitiba, PR, Brazil.
                [2 ]Department of Molecular Structural Biology and Genetics, State University of Ponta Grossa (UEPG), Ponta Grossa, PR, Brazil.
                Author notes
                [*Correspondence: ]veigass@ufpr.br.

                Competing interests: The authors declare that they have no competing interests.

                Authors’ contributions: SSV conceived this review. LHG and SSV coordinated the project. LHG, FHM, HCJ, ZSG, ABB, PHCS, IOL, MBF, ACMW, ASR and SSV wrote the paper. LHG, FHM, ASR and SSV participated in the revisions of it. All authors read and approved the final manuscript.

                Author information
                http://orcid.org/0000-0003-3347-4571
                http://orcid.org/0000-0001-9674-9996
                http://orcid.org/0000-0002-0158-8470
                http://orcid.org/0000-0002-8454-7454
                http://orcid.org/0000-0002-7967-6307
                http://orcid.org/0000-0002-9691-1225
                Article
                00205
                10.1590/1678-9199-JVATITD-2020-0188
                8314928
                34377142
                f69ed21c-7498-40c4-9236-483a767734df

                © The Author(s). 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 17 January 2021
                : 09 March 2021
                Page count
                Figures: 3, Tables: 1, Equations: 0, References: 123
                Categories
                Review

                astacins,serine proteases,serpins,knottins,tctp,hyaluronidases,allergens,spider venom

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