Role of Engineered Proteins as Therapeutic Formulations
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
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).
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].
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).
Exploitation of receptor tyrosine kinases by viral-encoded growth factors
Published in Growth Factors, 2018
A family of five VEGF ligands have been discovered in mammals, including VEGF-A, VEGF-B, placenta growth factor (PlGF), VEGF-C and VEGF-D (Olsson et al., 2006; Simons et al., 2016). These homodimeric glycoproteins share a cysteine knot motif comprising of three intertwining disulfide bridges. VEGF-A, and processed forms of VEGF-C and VEGF-D bind VEGFR2 within the extracellular Ig-like domains II-III (Figure 1). VEGF-A, VEGF-B and PlGF bind VEGFR1 within domains I-III. VEGF-C and VEGF-D bind domains I-II of VEGFR3. Selected isoforms of VEGF-A, PlGF and VEGF-B also interact with the co-receptor, neuropilin (NRP) 1 which increases their affinity for VEGFR1 or VEGFR2, while VEGF-C and VEGF-D also bind NRP2, primarily in association with VEGFR-3. Homologues of the mammalian VEGFR ligands have also been identified in genomes of viruses from the Poxviridae and Iridoviridae (Wang et al., 2007; Fleming et al., 2015), and in the venom from a range of snakes which have been reviewed elsewhere (Yamazaki & Morita, 2006). The next section will focus on the molecular and functional diversity of the viral ligands and their utility in dissecting the biological contributions of different VEGFRs.
Related Knowledge Centers
- Cyclotide
- Cysteine
- Disulfide
- Nerve Growth Factor
- Peptide
- Transforming Growth Factor Beta
- Structural Motif
- Inhibitor Cystine Knot
- X-Ray Crystallography
- Platelet-Derived Growth Factor