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The Development of Improved Therapeutics through a Glycan- “Designer” Approach
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Antimicrobial drug development no longer aims to only fight infections, but also to improve systemic health and reduce general drug toxicity/adverse effects. The interdisciplinary approach to new drug development aims at bringing all aspects of the immune system and linking pharmacological knowledge with biology of antigen processing and immunoregulation. In the past decade it became clear that glycosylation of both natural and synthetic antimicrobial peptides can influence antimicrobial activity, ability to enhance host immunity, improve target specificity, and peptide’s biological stability (Bednarska et al., 2017). Glycosylation had been described in five naturally occurring insect-derived AMPs (antimicrobial peptides/proteins), all O-linked, and proline-rich: diptericin, drosocin, formaecin, lebocin, and phyrrorricin. These observations and the availability of synthetic glycosylation allowed rapid synthetic antimicrobial glycopeptide development. Currently the glycobiology field is rapidly expanding with many synthetic approaches being implemented to generate large libraries of improved synthetic AMPs (Fig. 20.1).
The use of Drosophila melanogaster as a model organism to study immune-nanotoxicity
Published in Nanotoxicology, 2019
Cheng Teng Ng, Liya E Yu, Choon Nam Ong, Boon Huat Bay, Gyeong Hun Baeg
The homologs of Drosophila Toll have been identified in mammals and are now known as Toll-like receptors (TLRs) (Medzhitov et al. 1997). Sequence analysis of Toll gene in Drosophila revealed that its extracellular domain contains leucine-rich repeats and its intra-cytoplasmic region is highly similar to the cytoplasmic region of mammalian interleukin-1 receptor (IL-1R) (Medzhitov and Janeway, 2000; Hoffmann and Reichhart, 2002). Importantly, this implies that both human and Drosophila use Toll/IL-1R-induced activation of the NF-κB pathway for innate immunity (Belvin and Anderson, 1996). Furthermore, a study showed that the promoter regions of genes encoding for AMPs in Drosophila contain consensus NF-κB binding sites (Engstrom et al., 1993), suggesting the involvement of the Toll pathway in regulating the Drosophila immune system. This observation was then supported by flies with loss-of-function mutation in Toll which showed an increased susceptibility to fungal infection without impairing the responses to gram-negative bacterial infection (Lemaitre et al., 1996). AMPs are divided into three classes based on their lytic activity against pathogens. Drosomycin is an anti-fungal peptide, Diptericin works against gram-negative bacteria, and Defensin acts against gram-positive bacteria (Janeway and Medzhitov, 2002). The NF-κB family member Dif (Drosophila immunity factor) is required to induce Drosomycin via Toll (Rutschmann et al., 2000a). In Drosophila, activation of AMPs occurs via the NF-κB-like transcription factors, namely Dorsal and DIF. Hence, there is a striking homology in signaling components between mammals and Drosophila, although some homologs are positioned under different pathways. It is also worth to note that TIR domain of both systems (Toll and TLR) communicates via MyD88, which is a conserved molecule that ultimately activates the innate immune system (Figure 3).