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Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
Collectively, furin is an attractive therapeutic target for the development of novel antivirals that may be broadly effective to various infectious diseases. Peptide-based and small molecule inhibitors targeting furin/PCs have already been found to inhibit the syncytia formation effectively by blocking the SARS-CoV-2 S protein cleavage [90]. Thus these inhibitors may provide another tool to combat COVID-19 after further development.
Overview of Angiogenesis: Molecular and Structural Features
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
Arye Elfenbein, Michael Simons
More specifically, Notch signaling is responsible for the type of intercellular signaling that is known as lateral inhibition. This mode of developmental signaling enables different fates of differentiation to be selected within a homogenous group of cells (33). The Notch receptors (Notch 1–4) are cell membrane proteins that are cleaved upon binding of their (also membrane-bound) ligands, including Delta-1, -3, -4 and Jagged-1, -2, typically from another cell. Upon protein cleavage, the intracellular domain subsequently translocates to the nucleus and affects the transcription of target genes.
The role of apoptosis in non-mammalian host-parasite relationships
Published in G. F. Wiegertjes, G. Flik, Host-Parasite Interactions, 2004
One group of host proteins is a particular target for viruses. Caspases are activated by a variety of ‘death signals’, pro-caspases being cleaved at specific aspartic acid residues resulting in the production of two subunits. These subunits, acting as a tetramer, carry out the protein cleavage, which produces the typical apoptotic morphological changes in target cells. Several viruses, e.g. African swine fever virus and poxvirus produce gene products that inhibit the function of caspases. For example in cowpox the product termed cytokine response modifier A (CRMA), which is a serpin-like molecule, inhibits several caspases, e.g. 3, 6 and 8 in mammals but, interestingly, it also blocks apoptosis caused by synthesis of reaper in Drosophilia (see Villa et al., 1997).
Combining human platelet proteomes and transcriptomes: possibilities and challenges
Published in Platelets, 2023
Jingnan Huang, Johan W.M. Heemskerk, Frauke Swieringa
However, some limitations remain. Platelets and platelet proteins are highly sensitive to changes in the microenvironment during isolation, and react on factors such as temperature, pH, divalent cations, clotting and shear stress. This makes the pre-analytical preparation of platelet samples a critical issue. An issue complicating the isolation of platelets is their small volume (9–11 fL) and mass, when compared to erythrocytes (80–10 fL). Accordingly, care needs to be taken to minimize the contamination of a platelet preparation with erythrocytes and leukocytes. On the other hand, plasma proteins, being present in the platelet open canicular system can be considered as an integral part of platelets, implying that the full platelet proteome includes such proteins. Trypsin is being used as a gold standard for protein cleavage, but its activity needs to be precisely controlled to limit inter-sample variation. Other challenges are the identification of (very) low abundant proteins, of insoluble membrane proteins, the separation of sequence-related proteins, and a most reproducible analysis of highly complex mass spectra.
Granzyme B as a therapeutic target for wound healing
Published in Expert Opinion on Therapeutic Targets, 2019
Christopher T. Turner, Sho Hiroyasu, David J. Granville
As a consequence of granzyme B-mediated protein cleavage, peptide fragments are generated. Absent during immune cell maturation and development of tolerance, these peptides, with epitopes not typically exposed in healthy tissue, can trigger autoimmunity. Hundreds of novel, although non-validated granzyme B targets have been identified via proteomic analysis, including a large pool of previously undefined autoantigens [89]. Moreover, granzyme B is identified in one study as producing the majority of autoantigens targeted in systemic autoimmune diseases [90]. In scleroderma and systemic lupus erythematosus, two systemic autoimmune diseases, autoantigens specifically generated by granzyme B have been identified (reviewed in Darrah and Rosen, 2010) [90]. These autoantigens generated by granzyme B function to interfere with pathways of antigen presentation [90]. Patients with autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, typically display impaired wound healing phenotypes compared to control populations [91,92], possibly related to augmented inflammation and impaired and accelerated angiogenesis [92].
Cerliponase alfa for CLN2 disease, a promising therapy
Published in Expert Opinion on Orphan Drugs, 2020
Shawn C. Aylward, Jonathan Pindrik, Nicolas J. Abreu, W. Bruce Cherny, Matthew O’Neal, Emily de Los Reyes
Neuronal ceroid lipofuscinosis type 2 (CLN2) disease is a subtype of the collective family of neuronal ceroid lipofuscinosis or Batten’s disease. CLN2 is an ultra-rare autosomal recessive disorder occurring in 0.15 to 9.0 per 100,000 live births [1]. The disorder is caused by biallelic pathogenic variants in the gene encoding for the lysosomal enzyme tripeptidyl peptidase (TPP1), which is located on chromosome 11p15 [2,3]. This enzyme is activated within cellular lysosomes to allow protein cleavage into tripeptides. Lack or reduced effectiveness of this enzyme results in accumulation of autofluorescent ceroid lipofuscin in the intracellular space of neurons and other tissues. Over time, this accumulation results in progressive neuronal degeneration [2].