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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Cystine knot mini proteins (Knottins) are 30–50-amino-acid-long small proteins comprising a canonical cysteine knot. Structurally, knottins contain three antiparallel β-strands and are stabilized by three disulfide bonds arranged in a unique fashion. These bonds are formed between cys1 to cys 4, cys2 to cys5, and cys3 to cys6. The disulfide bond between cys3 to cys6 crosses a macrocycle formed by other two disulfide bonds and a backbone peptide bond. Together, these bonds form a cystine knot structure. Such a structure is responsible for higher thermal, chemical, and proteolytic stability of knottins. Cyclotides are a class of cystine knot proteins that undergo head to tail cyclization due to the presence of an extra loop in their structural architecture. Both knottins and cyclotides serve as promising candidates for potential therapeutic applications. External loops of both knottins and cyclotides make them amenable to various amino acid substitutions and also to the addition of various amino acids, rendering them structurally stable (Moore et al., 2012).
Antinociceptive peptides from venomous arthropods
Published in Toxin Reviews, 2023
Jessica A. I. Muller, Lai Y. Chan, Monica C. Toffoli-Kadri, Marcia R. Mortari, David J. Craik, Johannes Koehbach
Of all venomous animals, the phylum Arthropoda has the largest number of species compared with other phyla, and many of them produce toxins that are used for predation or protection (Haddad Junior et al.2015). This phylum comprises the classes Arachnida, Chilopoda, Diplopoda, Insecta and Crustacea (Figure 2) (Giribet and Edgecombe 2019). By far the most studied are venomous creatures that belong to Arachnida (e.g. scorpions and spiders) with around 90,000 species described (Coddington and Colwell 2013). The venomous Chilopoda (e.g. centipedes) and Insecta (e.g. bees, wasps and ants) are even more diverse with more than one million described species, and potentially many undiscovered species (Brown 2001, Minelli and Golovatch 2013), yet they are still the least studied classes of Arthropods (Senji Laxme et al.2019) (Figure 2). To date only one species of Crustacea (Speleonectes tulumensis) has been identified to be venomous, and functional activity studies confirming putative neurotoxic and/or antinociceptive properties are still missing. The authors describe an inhibitor cystine-knot (ICK) motif containing peptide with eight cysteines, similar to agatoxins described in spider venom (Von Reumont et al.2014).
VEGF-targeting drugs for the treatment of retinal neovascularization in diabetic retinopathy
Published in Annals of Medicine, 2022
Alessandro Arrigo, Emanuela Aragona, Francesco Bandello
VEGF, also known as vascular permeability factor, was firstly described as an endothelial cell-specific mitogen [3]. This group of molecules belong to the cystine-knot superfamily of hormones and extracellular signalling molecules, covering several functions in vertebrates [4]. VEGF is a dimeric glycoprotein of ∼40 kDa and is fundamental in promoting growth metabolic cascades and angiogenesis during the development of the vertebrate retina [5,6]. VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F, and PGF molecules. These mediators originate from the alternative splicing of a common source molecule and are further characterized by different isoforms [7]. Alternative splicing of the human VEGF-A gene provides at least six different isoforms, namely 121, 145, 165, 183, 189, and 206 [8]. VEGF-A121 and VEGF-A165 represent the most expressed forms in mammalians. With respect to VEGF-B, at least two isoforms are known, namely 167 and 186 [9]. On the other side, although largely studied in mouse models, less is known about the VEGF-C and VEGF-D isoforms [10–12]. VEGF-E is a molecule of ∼20 kDa, identified in the genome of Orf virus, a parapoxvirus that affects occasionally humans, generating lesions with angiogenesis [13], whereas VEGF-F is a toxin identified in the snake venom, having several similarities with the other VEGF isoforms [14].
Spider toxins targeting ligand-gated ion channels
Published in Toxin Reviews, 2021
Huwentoxin-I (HWTX-I) is the toxin for which some activity on nAChRs was suggested initially. The toxin is 33 amino-acid long, has six cysteines joined by three disulfide bridges (Liang et al. 1993). The structure is solved and the toxin demonstrates inhibitory cystine knot (ICK) (Qu et al. 1997), a common feature of spider toxins that enables them with high degree of stability (Craik et al. 2001).The toxin was isolated from the Chinese bird spider Haplopelma schmidti, and was shown to act on d-tubocurarine-sensitive nAChRs (Liang et al. 1993, Zhou et al. 1997). Later on, however, its binding to nAChRs was questioned (Liang et al. 2000): no binding of radiolabeled HWTX-I on Torpedo electric organ as well as no effect from toxin on muscle receptors of TE671 cell line were observed. Together with this, on three different preparations (guinea pig ileum, sympathetic neurons of rat vas deference, and toad heart) the blocking effect of the toxin was associated with presynaptic events (Liang et al. 2000), which later on was associated with toxin’s effect on voltage-gated calcium channels (Peng et al. 2001). Now it is established that Huwentoxin-I main activity is on N-type Calcium channels. And in this activity it is similar to ω-conotoxin MVIIA (Adams and Berecki 2013). The activity against insect receptors for Huwentoxin was shown on insect preparation (Wang et al.2012).