Disintegrate (DIN) Theory Enabling Precision Engineering of Proteins

Abstract

The chemical toolbox for the selective modification of proteins has witnessed immense interest in the past few years. The rapid growth of biologics and the need for precision therapeutics have fuelled this growth further. However, the broad spectrum of selectivity parameters creates a roadblock to the field's growth. Additionally, bond formation and dissociation are significantly redefined during the translation from small molecules to proteins. Understanding these principles and developing theories to deconvolute the multidimensional attributes could accelerate the area. This outlook presents a disintegrate (DIN) theory for systematically disintegrating the selectivity challenges through reversible chemical reactions. An irreversible step concludes the reaction sequence to render an integrated solution for precise protein bioconjugation. In this perspective, we highlight the key advancements, unsolved challenges, and potential opportunities.

Photoredox-catalyzed protecting-group-free C-glycosylation with glycosyl sulfinate via the Giese reaction

“…This methodology, using a water-soluble and bench-stable glycosyl donor, is expected to be widely available for the functionalization of water-soluble biomolecules such as nucleic acids and proteins. 26 Furthermore, application of conformational distribution analysis for the non-protected anomeric radicals, as described here, should contribute to the development of stereoselective functionalizations of anomeric radicals. Further application of this strategy to C-glycoside analogs of native glycoconjugates, as well as evaluation of the biological activities of the products, is underway in this laboratory.…”

Chemical technology principles for selective bioconjugation of proteins and antibodies

“…2). 8 Such a deconvolution can regulate chemoselectivity, site-selectivity, or protein specificity in distinct steps to offer better control over reaction parameters. Besides, it opens a gateway for a redefined reactivity landscape of proteins (compare routes A, B, C, and D; Fig.…”

Cross aldol OPAL bioconjugation outcompetes intramolecular hemiaminal cyclisation of proline adjacent N-terminal α-oxo aldehydes at acidic pH

“…Although highly effective, the modication of N-terminal a-oxo aldehydes has predominantly relied on aldehyde-heteroatom coupling chemistry 15 which affords linkages that have proved to be unstable in vivo, with damaging consequences. 16 This has motivated researchers to explore new approaches for the synthesis of more stable bioconjugates, recently leading to the development of methods for the construction of stable C-C bonds [17][18][19][20][21][22][23] using protein aldehydes as reaction partners. 24,25 Our own work in this eld has included the development of an organocatalystmediated protein aldol ligation (OPAL) 26 that efficiently affords a C-C linkage at neutral pH through cross aldol coupling of small molecule aldehyde donors and proteins bearing a-oxo aldehyde acceptors.…”