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Order Blubervirales: Core Protein
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
Sixth, a sortase-mediated site-specific tagging of antigens onto HBc VLPs was proposed (Tang S et al. 2016). In this strategy, the HBc molecule was split into two parts, aa 1–79 N-core and aa 80–183 C-core, by analogy with the SplitCore technique. The conserved LPETGG motif was fused to the C-terminus of the N-core to be exposed on the HBc VLPs surface and recognized by the transpeptidase, sortase A. The latter breaks the bond between threonine and glycine residues and links the cysteine 184 of sortase A to LPET. An acylated intermediate is formed at the “docking” step. Sortase A is then released from the VLP scaffold by peptides or proteins that harbor the N-terminal oligoglycines nucleophilic attack (Tian and Eriksson 2011). Hence, oligoglycine-based antigens are tagged on the N-LPETGG-C VLP surface at the “coupling” step. After docking and coupling, N-terminal oligoglycine-based antigens are conjugated to the surface of the N-LPETGG-C VLPs. Using this approach, Tang S et al. (2016) linked a protein from HCMV and two epitopes SP70 from VP2 of enterovirus 71, 15 aa with additional three glycines at the N-terminus, to the HBc VLPs.
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In an attempt to overcome the limitations associated with the chemical conjugation of small-molecule cytotoxic agents to antibodies such as the formation of heterogeneous ADCs with variable DARs, NBE Therapeutics Inc developed the SMACTM (Sortase Enzyme Mediated Antibody Conjugation) technology which can provide site-specific enzymatic conjugation of payloads to antibodies. It involves the use of a unique “sortase” enzyme to effect site-specific conjugation of payloads to antibodies, resulting in homogeneous ADCs with defined DARs. Due to the use of a mild enzymatic reaction that proceeds under physiological conditions, this conjugation methodology maintains the structure of the antibody in a fully intact state. A diagram of the methodology is provided in Figure 7.27. Diagram showing the enzymic attachment of a linker-payload construct to an antibody using the SMACTM (Sortase-enzyme Mediated Antibody Conjugation) methodology developed by NBE Therapeutics Inc. (Image drawn and kindly supplied by Peiqin Jin.)
Marine Natural Products for Human Health Care
Published in Hafiz Ansar Rasul Suleria, Megh R. Goyal, Health Benefits of Secondary Phytocompounds from Plant and Marine Sources, 2021
Jang et al. isolated [133] two bicyclic bromotyrosine-derived metabolites (pseudoceratins A and B) from Pseudoceratina sponge species (Pseudocera-tina purpurea); and both were active against Candida albicans [137]. Herpes simplex virus type 1 penetration was inhibited by 4-methylaaptamine, an alkaloid from the marine sponge Aaptos aaptos (EC50 = 2.4 μM) [277]. This sponge also yielded four aaptamines, which inhibited sortase A (an enzyme responsible for virulence and anchoring of cell wall proteins) in Staphylococcus aureus [134]. Bioactivity-guided fractionation of a marine sponge Spongosorites sp. yielded antimicrobial alkaloids in the class topsentin and hamacanthin [17]. Other anti-microbial alkaloids of sponge origin were found to have inhibitory activity against isocitrate lyase in Candida albicans [167].
Molecular engineering tools for the development of vaccines against infectious diseases: current status and future directions
Published in Expert Review of Vaccines, 2023
Wenhui Xue, Tingting Li, Ying Gu, Shaowei Li, Ningshao Xia
Sortase A, an enzyme superfamily widely distributed in Gram-positive bacteria, covalently attaches specific proteins to the bacterial cell wall [91]. In Staphylococcus aureus, Sortase A recognizes the LPXTG motif, cleaving between serine and glycine residues to create an acylated intermediate. This intermediate is then released through nucleophilic attack of oligoglycine and covalently linked to the amino group of pentaglycine in the cell wall crossbridge, resulting in cell wall-anchored proteins (Figure 2b) [92]. As a useful tool in protein site-specific modification, Sortase A has gained popularity in protein labeling and bispecific antibody research. Its site-specific properties make it an effective immunogen modification tool and a popular research target in molecular biology [93].
Inhibition of Streptococcus mutans adhesion and biofilm formation with small-molecule inhibitors of sortase A from Juniperus chinensis
Published in Journal of Oral Microbiology, 2022
Eunji Cho, Ji-Yeon Hwang, Jae Sung Park, Daehyun Oh, Dong-Chan Oh, Hyeung-Geun Park, Jongheon Shin, Ki-Bong Oh
Gram-positive pathogenic bacteria have many surface proteins related to bacterial adherence and host invasion, which play key roles in virulence. Sortase A (SrtA) is a transpeptidase that controls anchoring of surface proteins in the peptidoglycan cell walls of Gram-positive bacteria [1]. This protein recognizes the LPXTG motif in substrates, severs the amide bond between T and G residues, and forms a covalent bond between the substrate and cell wall [2]. Because numerous Gram-positive bacteria possess genes encoding SrtA and surface proteins with sorting signals recognized by SrtA, the SrtA-mediated anchoring system is considered a universal mechanism [3]. Knockout mutants of srtA fail to display surface proteins with the LPXTG motif which leads to diminished infectiousness without impacting bacterial viability [4–6]. For example, Staphylococcus aureus srtA mutants were not able to display Spa (protein A), FnbA (fibronectin-binding protein), ClfA (clumping factor) proteins, and showed impaired infections in mice [4]. Due to these properties, SrtA is closely associated with the virulence of Gram-positive pathogens and is considered a desirable anti-virulent drug target [7].
Molecular insights into probiotic mechanisms of action employed against intestinal pathogenic bacteria
Published in Gut Microbes, 2020
Winschau F. van Zyl, Shelly M. Deane, Leon M.T. Dicks
Previous studies suggested that sortase-dependent cell surface proteins (SDPs) play a crucial role in probiotic-host interactions, adherence and colonization.98–102 Several SDPs have been identified with a role in in vitro and in vivo adhesion to intestinal cells, including mucus-binding cell surface proteins Table 3. In Gram-positive bacteria, sortases decorate the cell surface with a diverse array of proteins by covalently joining them to the cell wall (Sortase A) or by polymerizing proteins to construct complex multi-subunit pilin structures (Sortase C) on the cell surface.99 Sortases are characterized as cysteine transpeptidases that join SDPs containing a specific cell wall sorting signal (CWSS) to an amino group located on the cell surface.100 Sortase A enzymes anchor proteins that contain a CWSS with a LPXTG (where X donates any amino acid) C-terminal motif to the cell surface.99 The LPXTG motif is recognized by the SrtA enzyme, which breaks the threonine and glycine peptide bond and then covalently links the threonine residue to the amino group of the pentaglycine bacterial cell wall cross bridge.93,101 Sortase C proteins catalyze a similar transpeptidation reaction, but recognize a QVPTGV sorting motif to construct pili that promote microbial adhesion.102 Using mutant analysis coupled with in vivo BLI, a recent study showed that E. mundtii ST4SA sortase mutants (srtA and srtC) had a reduced ability to exclude L. monocytogenes EGDe from the GIT of mice compared to the wild-type derivative.37