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A Scalable Design for Proximity-Inducing Molecules
Endri Karaj1,2, Varsha Venkatarangan1,3,4,2, Shaimaa H Sindi1,2
1Chemical Biology and Therapeutics Science, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Biorxiv : the Preprint Server for Biology
|February 27, 2026
Summary
We developed GRoup-transfer chimeras for Inducing Proximity (GRIPs), a scalable platform for modifying proteins. GRIPs utilize abundant effector inhibitors to precisely edit post-translational modifications (PTMs) for new therapeutic applications.
Area of Science:
- Biochemistry
- Chemical Biology
- Molecular Biology
Background:
- Chimeric molecules, like PROTACs, enable targeted protein modification by linking effector enzymes with proteins-of-interest (POIs).
- Current chimera technologies face scalability limitations due to reliance on rare, non-inhibitory effector binders.
Purpose of the Study:
- To develop a scalable and versatile platform for protein post-translational modification (PTM) editing.
- To engineer novel chimeras using abundant effector inhibitors for enhanced therapeutic applications.
Main Methods:
- Development of GRoup-transfer chimeras for Inducing Proximity (GRIPs) using effector inhibitors and group-transfer handles.
- Creation of 6 GRIPs classes across 3 PTMs, testing 16 effector-POI pairs, and a toolbox of 42 group-transfer handles.
- Utilizing global proteomics to confirm specificity and employing GRIPs in endogenous and tagged protein systems.
Main Results:
- Demonstrated scalability of GRIPs across diverse PTMs and effector-POI pairs.
- Confirmed specificity of group transfer and PTM editing via proteomics.
- Showcased novel functionalities including sustained inhibition, prevention of rebound signaling, and pathway activation in endogenous systems.
- Achieved condensate formation, pathogenic PTM clearance, and PTM crosstalk initiation in hemi-endogenous systems.
Conclusions:
- GRIPs offer a scalable and adaptable platform for precise PTM editing.
- This technology enables new therapeutic strategies by imparting novel functionalities to POI drugs.
- GRIPs advance the field of targeted protein modification with broad applicability.
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