Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Jan 23;9(2):137-150.
doi: 10.1021/acscentsci.2c01455. eCollection 2023 Feb 22.

D is in tegrate (DIN) Theory Enabling Precision Engineering of Proteins

Preeti Chauhan  1 , Ragendu V  1 , Mohan Kumar  1 , Rajib Molla  1 , Unnikrishnan V B  1 , Vishal Rai  1
Affiliations
Review

D is in tegrate (DIN) Theory Enabling Precision Engineering of Proteins

Preeti Chauhan et al. ACS Cent Sci. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
(a) The microenvironment of a functionality (nucleophile, Nu) from small molecules to a complex protein-based social ecosystem. (b) DIN theory: the disintegration of reaction attributes and their independent regulation can empower the integration of solutions for the precision engineering of native proteins.
Figure 2
Figure 2
Disintegration of selectivity attributes through chemical steps redefines the reactivity landscape to enable single-site protein modification. (a) Targeting reactivity hotspots in one step. (b) A two-step process, reversible intermolecular and irreversible intermolecular, can deconvolute chemoselectivity and site selectivity to render redefined reactivity hotspots. (c) A two-step process, reversible intermolecular and irreversible intramolecular, can offer modularity in addition to chemoselectivity and site selectivity deconvolution. (d) A multistep process can deconvolute chemoselectivity and residue specificity. The selected routes a–d show representative possibilities and can be extended to other reagent and intermediate combinations.
Figure 3
Figure 3
Targeting reactivity hotspots in one step: efforts with Arg, carboxylates, Cys, and His.
Figure 4
Figure 4
Targeting reactivity hotspots in one step: efforts with Lys, N-terminus amine, Met, Trp, and Tyr.
Figure 5
Figure 5
Ligand-enabled localization reduces competitors and empowers the single step for the selective labeling of proteins.
Figure 6
Figure 6
Route B: a two-step process can deconvolute chemoselectivity and site selectivity to render redefined reactivity hotspots.
Figure 7
Figure 7
Route C: a two-step process can offer modularity in addition to chemoselectivity and site selectivity deconvolution.
Figure 8
Figure 8
Route C: a two-step process can offer N-terminal specific modification.
Figure 9
Figure 9
Route D: a multistep process can deconvolute chemoselectivity and residue specificity.
See this image and copyright information in PMC

References

    1. Leader B.; Baca Q. J.; Golan D. E. Protein Therapeutics: A Summary and Pharmacological Classification. Nat. Rev. Drug Discovery 2008, 7 (1), 21–39. 10.1038/nrd2399. - DOI - PubMed
    1. Bull S. C.; Doig A. J. Properties of Protein Drug Target Classes. PLoS One 2015, 10, e0117955.10.1371/journal.pone.0117955. - DOI - PMC - PubMed
    1. Hughes J. P.; Rees S.; Kalindjian S. B.; Philpott K. L. Principles of Early Drug Discovery. Br. J. Pharmacol. 2011, 162 (6), 1239–1249. 10.1111/j.1476-5381.2010.01127.x. - DOI - PMC - PubMed
    1. Drewes G.; Knapp S. Chemoproteomics and Chemical Probes for Target Discovery. Trends Biotechnol. 2018, 36 (12), 1275–1286. 10.1016/j.tibtech.2018.06.008. - DOI - PubMed
    1. Vasta J. D.; Peacock D. M.; Zheng Q.; Walker J. A.; Zhang Z.; Zimprich C. A.; Thomas M. R.; Beck M. T.; Binkowski B. F.; Corona C. R.; Robers M. B.; Shokat K. M. KRAS Is Vulnerable to Reversible Switch-II Pocket Engagement in Cells. Nat. Chem. Biol. 2022, 18 (6), 596–604. 10.1038/s41589-022-00985-w. - DOI - PMC - PubMed