Our Science

Precision-Linked Proteomimetics™ : A Novel Platform for Targeting Intracellular Protein-Protein Interactions

Precision-Linked Proteomimetics^TM (PLPs) are customizable, synthetic, multivalent, protein-scale “proteomimetics” with the selectivity, potency and cell-permeability needed to engage intracellular targets.

Breakthrough Plug-and-Play Design

allows customization for any target

Dynamic Protein-Scale Architecture

confers cell permeability, solubility and potency (avidity)

Accelerated Drug Discovery

with potent, cell-active molecules “out of the box”

Breakthrough Plug-and-Play Design Allows Customization for Any Target

PLPs are built from modular building blocks. The Target-Binding Peptide Domain can be identified through structural biology, antibody CDR domain or phage display technology and “plugged” into the building block. Pharmacologic properties can be optimized by modifying the Linker and Design Module, while preserving target-binding activity. These building blocks are joined together through precision polymerization of the backbone precursors to form a PLP. Synthesis is highly controlled and reproducible, yielding discrete, multivalent, protein-scale molecules that can be monofunctional or bifunctional.

Dynamic Protein-Scale Architecture Enables Both Solubility and Cell Permeability

PLPs are globular, yet flexible and undergo proximity-induced changes in conformation. Polar, hydrophilic groups are exposed in aqueous solution to promote solubility. Upon engagement with a cell membrane, the high-density, flexible peptide array enables polar surface masking, while the hydrophobic backbone favorably interacts with the lipophilic membrane.

Space-filling model

Molecular dynamics simulation

Accelerated Drug Discovery

The PLP platform technology transforms peptides into cell-active compounds with key pharmacologic properties. PLPs display cell permeability, potency and long half-life “out of the box”, bypassing some of the most challenging hurdles of traditional drug discovery workflows. In vitro validation of on-target and on-mechanism activity can be achieved in weeks to months.

Peptide Input

PLP

Peptide Hit

PLP Lead

Selected Publications

Angela P. Blum, Jacquelin K. Kammeyer and Nathan C. Gianneschi. “Activating peptides for cellular uptake via polymerization into high density brushes” Chem. Sci., 2016, 7, 989-994. DOI: 10.1039/C5SC03417E (Open Access).
Cassandra Callmann, Matthew Thompson and Nathan Gianneschi. "Poly(peptide): Synthesis, Structure, and Function of Peptide-Polymer Amphiphiles and Protein-like Polymers" Accounts of Chemical Research, 2020. 53 (2) 400-413. DOI: 10.1021/acs.accounts.9b00518.
Kendal P. Carrow, Haylee L. Hamilton, Madeline P. Hopps, Yang Li, Baofu Qiao, N. Connor Payne, Matthew P. Thompson, Xiaoyu Zhang, Assa Magassa, Mara Fattah, Shivangi Agarwal, Michael P. Vincent, Marina Buyanova, Paul A. Bertin, Ralph Mazitschek, Monica Olvera de la Cruz, Delinda A. Johnson, Jeffrey A. Johnson, and Nathan C. Gianneschi. "Inhibiting the Keap1/Nrf2 Protein-Protein Interaction with Protein-Like Polymers" Adv. Mater., 2024, 2311467. DOI: 10.1001/adma.202311467 (Open Access).