Proximity-Based Modalities for Biology and Medicine

Xingui Liu; Alessio Ciulli

doi:10.1021/acscentsci.3c00395

Proximity-Based Modalities for Biology and Medicine

Xingui Liu, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

54 Citations (Scopus)

133 Downloads (Pure)

Abstract

Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high selectivity and has the potential to substantially expand the target space. A plethora of proximity-based modalities to target proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines the diverse mechanisms and molecules based on induced proximity, including protein degraders, blockers, and stabilizers, inducers of protein post-translational modifications, and agents for cell therapy, and discusses opportunities and challenges that the field must address to mature and unlock translation in biology and medicine.

Original language	English
Pages (from-to)	1269-1284
Number of pages	16
Journal	ACS Central Science
Volume	9
Issue number	7
Early online date	14 Jul 2023
DOIs	https://doi.org/10.1021/acscentsci.3c00395
Publication status	Published - 26 Jul 2023

Keywords

Cells
Degradation
Ligands
Molecules
Peptides and proteins

ASJC Scopus subject areas

General Chemical Engineering
General Chemistry

Access to Document

10.1021/acscentsci.3c00395Licence: CC BY

Final Published VersionFinal published version, 9.45 MBLicence: CC BY

Cite this

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title = "Proximity-Based Modalities for Biology and Medicine",

abstract = "Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high selectivity and has the potential to substantially expand the target space. A plethora of proximity-based modalities to target proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines the diverse mechanisms and molecules based on induced proximity, including protein degraders, blockers, and stabilizers, inducers of protein post-translational modifications, and agents for cell therapy, and discusses opportunities and challenges that the field must address to mature and unlock translation in biology and medicine.",

keywords = "Cells, Degradation, Ligands, Molecules, Peptides and proteins",

author = "Xingui Liu and Alessio Ciulli",

note = "Funding Information: Research in the Ciulli laboratory on targeted protein degraders, PROTACs, and molecular glues receives funding from the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under Grant 875510 (EUbOPEN project). The IMI2 Join Undertaking receives support from the European Union{\textquoteright}s Horizon 2020 research and innovation program, EFPIA companies, and associated partners: KTH, OICR, Diamond, and McGill. A.C. is also very grateful to the many organizations that currently fund or have funded research in his laboratory over many years, including the U.K. Biotechnology and Biological Sciences Research Council (BBSRC) and other UK Research Councils, the European Research Council (ERC), the European Commission, and pharmaceutical companies Almirall, Amgen, Amphista Therapeutics, Boehringer Ingelheim, GlaxoSmithKline, Eisai, Merck KGaA, Nurix Therapeutics, Ono Pharmaceuticals, and Tocris-Biotechne. X.L. is funded by a UKRI Postdoc Guarantee fellowship (EP/X025225/1) and was previously funded through a Rising Star Fellowship from Ono Pharmaceutical. Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society.",

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doi = "10.1021/acscentsci.3c00395",

language = "English",

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AB - Molecular proximity orchestrates biological function, and blocking existing proximities is an established therapeutic strategy. By contrast, strengthening or creating neoproximity with chemistry enables modulation of biological processes with high selectivity and has the potential to substantially expand the target space. A plethora of proximity-based modalities to target proteins via diverse approaches have recently emerged, opening opportunities for biopharmaceutical innovation. This Outlook outlines the diverse mechanisms and molecules based on induced proximity, including protein degraders, blockers, and stabilizers, inducers of protein post-translational modifications, and agents for cell therapy, and discusses opportunities and challenges that the field must address to mature and unlock translation in biology and medicine.

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Proximity-Based Modalities for Biology and Medicine

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

EUbOPEN: Enabling and Unlocking biology in the OPEN (Joint with Goethe University Frankfurt, University of Oxford, Karolinska Institute and 9 others)

Development of LRRK2 PROTAC degraders as chemical probes and potential lead compounds for the treatment of Parkinson’s disease (PROCESS)

Cite this

Proximity-Based Modalities for Biology and Medicine

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

EUbOPEN: Enabling and Unlocking biology in the OPEN (Joint with Goethe University Frankfurt, University of Oxford, Karolinska Institute and 9 others)

Development of LRRK2 PROTAC degraders as chemical probes and potential lead compounds for the treatment of Parkinson’s disease (PROCESS)

Cite this