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Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Monobodies are the protein scaffolds based on Fibronectin type III domain. Fibronectin is a large protein that interacts with the extracellular matrix proteins and regulates cell-cell communication. Structurally, it is a large protein containing two 250 kD subunits connected by disulfide bridges. These subunits contain the repeats of three domains (type I, II, III). The first monobody was engineered using the tenth repeat of type III domain of Fibronectin (FNfn10) against ubiquitin using phage display system. FNfn10 is devoid of disulfide bonds, and also contains 7 β-strands and 3 surface loops that can be used to add diversity to the monobodies. Their structural simplicity makes them compatible with any screening method such as phage display, yeast two-hybrid system, and peptide-ribonucleic acid. They can be expressed in large quantities in bacteria and are highly thermo stable (Koide and Koide, 2007). Such properties of monobodies make them ideal candidates for therapeutic protein scaffolds. Monobodies have been engineered for the numerous proteins including EGFR (Hackel et al., 2012), IL-23 (Tang et al., 2012), Ableson (Abl) kinase SH2 domain (Wojcik et al., 2010), etc.
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
Peptide-based drugs, including the staple peptide SAH-SOS1[37], the hydrogen bond surrogate peptide[36], and a series of macrocyclic peptide inhibitors, such as cyclorasin 9A5[38], were potent RAS inhibitors generated from display libraries. Protein-based drugs that impair RAS PPI interface with RAF/PI3K/SOS were developed, for example, the antibody mimetics DARPin K27 discovered via phage/cell-surface display technologies[54]. Another monobody named NS1 binds to the dimerization interface of RAS and attenuates RAS downstream pathways in an allosteric manner[55]. Besides, combinatorial therapies could be applied for targeting RAS, including inhibition of downstream effectors, inhibition of synthetic lethal interactions and inhibition of RAS-related metabolism [10,99].