Peptides

SARS-inhibitor 4

Amino acids 45-73, derived from the exon 2/insert 1 domain, of tubulin-associated unit (tau). Tau is a phosphoprotein protein involved in microtubule (MT) assembly and stability as well as brain development. Tau is phosphorylated at multiple sites by several protein kinases, including cyclic-AMP-dependent protein kinases and casein kinase type-1. Tau phosphorylation causes tau to change shape negatively regulating its ability to stimulate MT assembly. Tau is also glycosylated, and O-glycosylation may have a role in its subcellular localisation and degradation.Malfunctioning tau protein contributes to the structural core of the paired helical filaments (PHFs), which make up neurofibrillary tangles (NFTs). NFTs are often observed in neurodegenerative disorders, such as Alzheimer disease and other tauopathies. Tau is expressed from a single gene and is alternatively spliced to yield six different isoforms in the adult central nervous system (CNS).

Adrenomedullin (ADM), is a free circulating peptide of the amylin/calcitonin gene-related peptide (CGRP) super-family. It is widely expressed in virtually all human tissues and is involved in regulation of endothelial barrier function- vascular tone- immunoregulation- cellular proliferation and apoptosis. ADM is implicated in the pathophysiology of several diseased states including: sepsis- heart failure- inflammatory bowel disease- diabetes- eye pathologies and many cancers. ADM levels are often increased during these diseased states often correlating with disease severity and mortality. ADM is therefore of interest as a target for these diseases. ADM also displays potent antimicrobial action against Gram-positive and Gram-negative bacteria.The 52 amino acid ADM is produced by multiple cleavage steps from the original 85 amino acid long preprohormone (prepro-ADM). ADM exerts its effects by ligation of receptor complexes consisting of the calcitonin receptor-like receptor (CRLR) combined with a specific receptor activity-modifying protein (RAMP). Interaction of ADM with its receptor occurs through its C-terminal moiety.

Temporin L is a highly potent anti-microbial peptide (AMP) active against both Gram-positive and Gram-negative bacteria. Temporins are a large family of short, linear, AMPs produced in the skin of frogs belonging to Rana species, but are also found in wasp venom. Temporin L was originally isolated from the frog Rana temporaria and has the highest anti-microbial potency among tested temporins, especially against Gram-negative bacteria.Temporin L increases bacterial inner membrane permeability in a dose-dependent manner without destroying cell integrity. At low peptide concentrations, the inner membrane becomes permeable to small molecules but this does not kill the bacteria. At high concentrations, larger molecules, but not DNA, leak out, resulting in cell death. Temporin L has a different mode of action to many AMPs as it does not lyse the cells but instead forms ghost-like bacteria shells.

Farnesylated a-factor is a post-translationally modified mating pheromone derived from Saccharomyces cerevisiae. The addition of a farnesyl group to the C-terminus is crucial for the biological activity of the a-factor.During the mating of Saccharomyces cerevisiae, the haploid state of yeast can be either α-type or a-type. Mating pheromones produced by these haploid cells can induce two different cell types to mate. The α-factor is released from α-type cells and bind to the G-protein coupled receptor (GPCR) Ste2p on a-cells, whereas the a-factor is released from a-type cells and binds to the GPCR Ste3p on α-cells.

Influenza virus budding from infected cells requires membrane remodelling, is a multistep process with many proteins involved. Therefore there are numerous stages and proteins that could be antiviral targets if the mechanism can be better understood.The matrix 2 (M2) protein has recently been shown to be essential for completion of membrane scission at the end of buddinng. Initially, proteins aid membrane curvature, including matrix 2 (M2) protein, a bud forms, and finally membrane scission occurs to release the bud at the neck from the membrane occurs- M2 amphipathic helix domain in the cytoplasmic tail is essential for completion of scission to release the virus bud. The residues 44-62, provided here, have been identified as the motif responsible for allowing the scission mechanism to occur. Work is ongoing to understand the exact molecular mechanism by comparison to other scission proteins such as Arf1, Epsin1. Use of this M2 peptide motif may provide functional knowledge of virus budding and lead to novel antiviral drugs.

VP4 is a viral coat protein of Nora virus encoded for by ORF4. The product of this gene is likely cleaved into three capsid proteins, VP4A, B and C. VP4 is also the most conserved gene from Nora virus and related viruses. Nora virus is a non-pathogenic virus found in gut of Drosophila melanogaster. It causes persistent, non-pathological infection, it replicates in the fly gut and is transmitted via the faecal-oral route. Nora virus has a 12333 nucleotides long single-stranded RNA genome of positive polarity.

The Histone H3 (22-30)-K27Me3 is derived from Histone 3 (H3) which is one of the four core histones (H2A, H2B, H3 and H4) fundamental in compacting eukaryotic DNA into the nucleosome. The nucleosome arises when 147 base pairs of DNA wrap around a H3-H4 tetramer and two H2A-H2B dimers, forming the histone octamer core. Both H4 and H3 are highly conserved and perform roles in binding to segments of DNA which enter and leave the nucleosome and in chromatin formation. Similar to the other core histone, H3 has a globular domain and a flexible N-terminal domain, 'histone tail' which can undergo modifications such as acetylation, methylation, phosphorylation and ubiquitination. Due to histones containing a large number of lysine and arginine residues they have a positive net charge which interacts in an electrostatic manner with the negatively charged phosphate groups in DNA. The transcriptional activation or silencing of the chromatin is controlled by ATP-dependent chromatin remodelling factors and histone modifying enzymes which target histone proteins. Both processes function to alter to change the positioning of the nucleosome, allowing the DNA it to be either available to the transcription machinery or inaccessible.The Histone H3 (20-36) lysine 27 has been trimethylated which is usually a marker of repressive chromatin. H3K27 trimethylation also prevents H3 from interacting with SET1-like complexes, thus inhibiting the trimethylation of H3K4.

The SARS-CoV-2 spike protein is present on the outside of the virus particles and can bind to angiotensin-converting enzyme II (ACE2) present on the host cells. The C-terminal receptor binding domain (RBD) of the spike protein binds to the N-terminal peptidase M2 domain of ACE2. This receptor binding results in the internalisation of the virus-receptor complex and is, therefore the mechanism of entry of SARS-CoV-2 into host cells.The spike protein residues VQIDRLITGR (991-1000) from SARS-CoV-2 have been identified as a T-cell epitope with a predicted HLA restriction. Immune targeting of confirmed epitopes may potentially offer protection against SARS-CoV-2 and help the development of vaccines for long-lasting immunity.