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, 11 (4), 42-53

DARPins: Promising Scaffolds for Theranostics

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DARPins: Promising Scaffolds for Theranostics

O N Shilova et al. Acta Naturae.

Abstract

Monoclonal antibodies are the classical basis for targeted therapy, but the development of alternative binding proteins has made it possible to use non-immunoglobulin proteins as targeting modules. The advantages of DARPins, scaffold proteins based on ankyrin repeats, over antibodies are as follows: small size, stability over a wide range of temperatures and pH values, low aggregation tendency, and ease of production in heterologous expression systems. The differences in the structure of the paratope of DARPin and antibodies broaden the spectrum of target molecules, while the ease of creating hybrid fusion proteins allows one to obtain bispecific and multivalent constructs. In this article, we summarize recent data on the development of therapeutic and imaging compounds based on DARPins.

Keywords: DARPin; barnase; targeted therapy.

Figures

Fig. 1
Fig. 1
The structure of DARPins. A – the structure of the consensus ankyrin repeat; the constant part is shown in gray; the variable regions are shown in red. B – the structure of a DARPin molecule. Two or three binding motifs form the binding surface through variable amino acids (shown in red); the hydrophobic regions are shielded by the C-cap and N-cap. C – 3D structure of a DARPin molecule, the variable amino acids are shown in red
Fig. 2
Fig. 2
Application of DARPins in cancer cell visualization and elimination. DARPins can inhibit cell signaling molecules, thus suppressing cell proliferation, or serve as targeting modules for the delivery of various agents: radionuclides, nanoparticles or liposomes, photosensitizers, protein toxins, oncolytic viruses, and lymphocytes with chimeric antigenic receptors. HER2 – human epidermal growth factor receptor 2; NP – nanoparticle; ROS – reactive oxygen species; PI3K – phosphoinositide-3-kinase; Ras – small GTPase Ras; CAR – chimeric antigen receptor; CAR-T – T-lymphocyte expressing the chimeric antigen receptor; FAS – death receptor (CD95, APO-1), an inducer of extrinsic apoptosis pathway; FASL – ligand of the FAS receptor (CD95L, CD178); ETA – truncated Pseudomonas aeruginosa exotoxin A

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