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Computational Biology and Bioinformatics in Anti-SARS-CoV-2 Drug Development
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Obviously, the host receptor(s) responsible for virus binding should be considered as primary target(s) for drug development, since blocking or disturbing virus-receptor interactions should reduce or prevent virus entry. In COVID-19, the main virus receptor is angiotensin-converting enzyme 2 (ACE2), whose activity is related to the renin–angiotensin system (RAS) involved in the maintenance of blood pressure homeostasis, and fluid and salt balance [106]. Another important host target is transmembrane serine protease 2 (TMPRSS2), as following receptor interaction, specific cleavage of viral S protein at the S1/S2 site by this protease can activate the virus–host cell membrane fusion for subsequent genome delivery [107]. The S protein of SARS-CoV-2 contains a specific multi-basic furin-like cleavage site [108, 109], which is not found in other CoVs [110]. Furin, which is a type 1 membrane-bound protease from the subtilisin-like proprotein convertase family expressed in multiple tissues, serves as another attractive drug target [87]. It was pointed out that while the furin-like enzymes play a pleiotropic role in a large number of cellular processes, drugs targeting this protein might show noticeable side effects [111].
Introduction to Bioresponsive Polymers
Published in Deepa H. Patel, Bioresponsive Polymers, 2020
Deepa H. Patel, Drashti Pathak, Neelang Trivedi
A member of the pro-protein convertase family, furin has a key role in tumor development, metastasis, and angiogenesis. In one investigation, a furin-cleavable peptide cross-linker was fused with drug-delivery carriers, which could be degraded gradually to release payload protein along their cellular uptake pathway [44]. In a recent investigation, a graphene-based co-delivery system took benefit of the trans-membrane activity of furin to cleave the furin-degradable substrate for the exposure of TRAIL in the direction of the membrane [45].
Reduction and Fixation of Sacroiliac joint Dislocation by the Combined Use of S1 Pedicle Screws and an Iliac Rod
Published in Kai-Uwe Lewandrowski, Donald L. Wise, Debra J. Trantolo, Michael J. Yaszemski, Augustus A. White, Advances in Spinal Fusion, 2003
Kai-Uwe Lewandrowski, Donald L. Wise, Debra J. Trantolo, Michael J. Yaszemski, Augustus A. White
TGF- β1 is the proteotypic member of the TGF β1superfamily consisting of activins, inhib-ins, mullerian-inhibiting substance, other TGF- β1 and bone morphogenetic proteins (BMPs). This family of over 40 related growth and differentiation factors has gained many new members since the discovery of TGF- βl (Fig. 6) [11]. TGF- β1 is synthesized as part of a larger inactive protein consisting of two disulfide linked, cy steine-rich 12-15 kDa polypeptides. Furin proteases activate this precursor molecule through enzymatic cleavage and release of the biologically active C-terminal region [12]. It is this active protein that serves as a potent osteoactive factor.
Drug repurposing strategies and key challenges for COVID-19 management
Published in Journal of Drug Targeting, 2022
Shubham Mule, Ajit Singh, Khaled Greish, Amirhossein Sahebkar, Prashant Kesharwani, Rahul Shukla
Furin-like cleavage site (FCS) has recently been discovered in the spikes morphology of SARS-CoV-2, imparting greater virulence [24]. The FCS was absent in SARS-CoV2, hence it may be regarded as the important indicator for the evolution of the virus [25]. In an investigation conducted on samples obtained from COVID-19 affected individuals from the Zhejiang province of China, it was found that the mutations at the FCS region of spike protein altered its ability to bind with furin [54]. However, FCS concentration is lower in the lungs as compared to other organs like the kidney, colon and liver which may point towards the FCS being a contributing factor for infection to these organs [25]. On the other hand, the interaction between furin and ACE2 exhibiting a parallel relationship between various clinical aspects of infection in different populations and the activity of furin in them has also been reported [55,56]. In view of the above-mentioned role of furin, its inhibition may support the arrest of viral growth when used in combination with other therapeutic agents. However, furin possesses a diverse role in the physiological system, especially in cellular processes, hence its inhibition may invite systemic side effects [57].
Dendritic cells in COVID-19 immunopathogenesis: insights for a possible role in determining disease outcome
Published in International Reviews of Immunology, 2021
Rodrigo Cerqueira Borges, Miriam Sayuri Hohmann, Sergio Marques Borghi
In addition to DC-SIGN, other host factors such as furin enzyme, have been implicated in successful SARS-CoV-2 entry and replication in cells [65]. Furin is a proprotein convertase responsible for processing latent proteins into its active forms [66], contributing to the cleavage of viral proteins and bacterial endotoxins [67, 68]. A recent report demonstrates that monocyte derived-dendritic cells and macrophages from healthy human volunteers are permissive to SARS-CoV-2 infection and viral protein expression, but did not support productive SARS-CoV-2 replication [69]. Interestingly, SARS-CoV-2-infected monocyte-derived dendritic cells presented a robust increase of furin and DC-SIGN expression, which was not observed in the same magnitude after SARS-CoV infection [69], suggesting that SARS-CoV-2 can modulate monocyte-derived dendritic cells to facilitate infection.
Emerging Human Coronavirus Infections (SARS, MERS, and COVID-19): Where They Are Leading Us
Published in International Reviews of Immunology, 2021
Myeloid cells, including macrophages and neutrophils, also express furin [223,224]. The deletion of furin in peritoneal macrophages upregulates the Serpinb1a (Serine [or cysteine] peptidase inhibitor, clade B, member 1a), Serpinb2 (Serine peptidase inhibitor, clade B [Ovalbumin], member 2), Hcar2 (Niacin Receptor 1), Egr1 (Early growth response 1), Il6, Il1β, Ptgs2 (Cyclooxygenase II), Ccl2, Ccl7 and C5ar1 (Complement 5a receptor 1) expression, like activated macrophages [224]. Thus under homeostasis furin expression serves as an endogenous negative regulator of gene expression associated with pro-inflammatory M1 macrophages. The anti-inflammatory action of furin can be seen during TLR4, TLR2, and TLR7/8 activated macrophages [224]. However, the lack of furin on macrophages decreases the IL-10 production upon TLR4 stimulation. Endogenous factors, including IFN-γ, TGFβ1 (also serves as its substrate), and IL‐12 increase the furin expression [225,226]. Furin is located at TGN, endosomes, at the cell surface, and in the extracellular space. A proline insertion in this polybasic furin cleavage site is also reported and called PRRA, which is unique to SARS-CoV2 [227]. However, the function of the polybasic furin site in SARS-CoV2 is not known but may be involved in increasing its transmissibility and pathogenesis. For example, SARS-CoV with furin cleavage site at S1 and S2 junction enhances cell-cell junction without affecting the virus entry into the host cell [228].