Abstract
Chemoselective ligations allow chemical biologists to functionalise proteins and peptides for biomedical applications and to probe biological processes. Coupled with solid phase peptide synthesis, chemoselective ligations enable not only the design of homogeneous proteins and peptides with desired natural and unnatural modifications in site-specific locations but also the design of new peptide and protein topologies. Although several well-established ligations are available, each method has its own advantages and disadvantages and they are seldom used in combination. Here we have applied copper-catalyzed azide-alkyne “click,” oxime, maleimide, and native chemical ligations to develop a modular synthesis of branched peptide and polymer constructs that act as cancer-targeting immune system engagers (ISErs) and functionalised them for detection in biological systems. We also note some potential advantages and pitfalls of these chemoselective ligations to consider when designing orthogonal ligation strategies. The modular synthesis and functionalization of ISErs facilitates optimisation of their activity and mechanism of action as potential cancer immunotherapies.
Highlights
The use of antibodies for cancer therapy takes advantage of the specific binding of antibodies to their targets and has led to the introduction of several antibody-based cancer therapeutics into the clinic (Scott et al, 2012; Sliwkowski and Mellman, 2013)
We have previously reported the development of a prototype innate immune system engager (ISEr), a peptide-polymer conjugate that mimics the functions of antibodies in targeting cancer cells and eliciting an immune response (Brehs et al, 2017) immune system engagers (ISErs) are synthesized entirely by solid phase peptide synthesis (SPPS) and comprise two or more “binder” peptides that target receptors overexpressed on cancer cells and are conjugated via polyethylene glycol (PEG) linkers to an “effector” peptide that stimulates an immune response (Figure 1) (Brehs et al, 2017)
We sought to develop a modular synthesis of ISErs that would enable the attachment of several different binder peptides to the same peptide-polymer scaffold using chemoselective ligations, so that multiple binders could be tested rapidly
Summary
The use of antibodies for cancer therapy takes advantage of the specific binding of antibodies to their targets and has led to the introduction of several antibody-based cancer therapeutics into the clinic (Scott et al, 2012; Sliwkowski and Mellman, 2013). Peptides and peptide-polymer conjugates can mimic the functions of large folded proteins such as antibodies and have the advantage that they are synthetically accessible and readily modified and optimized for specific biological functions (Ahrens et al, 2012; Fosgerau and Hoffmann, 2015; Gross et al, 2015; Conibear et al, 2017a). We have applied the chemoselective reactions above for the functionalization of peptide-polymer scaffolds that mimic the functions of natural antibodies, enabling modular syntheses and rapid optimisation and modification
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