Computationally-guided design of peptoid oligomer binders for therapeutic targets

Overview

This research program offers a powerful approach for discovering highly selective peptoid-based molecular binders targeting heparan sulfate, sphingolipids, and lysosomal proteins. Peptoids are biocompatible synthetic oligomers that combine the molecular recognition capabilities of peptides with significantly enhanced stability and reduced immunogenicity. The platform integrates computational library screening of peptoid side chains with one-bead-one-compound experimental screening of peptoid libraries, enabling efficient identification of high-affinity binders for challenging therapeutic targets.

The technology addresses critical needs in drug discovery by providing access to molecules that can cross the blood-brain barrier, resist enzymatic degradation, and offer peptide-like specificity without immunogenic concerns. By targeting heparan sulfate, sphingolipids, and lysosomal proteins, the platform opens pathways to treatments for a range of diseases including lysosomal storage disorders, neurological conditions, and metabolic diseases.

Technical specifications

Key capabilities:

• Dual design strategy: Combines computationally-guided peptoid side chain design with a side-chain similarity approach that mimics known peptide binders
• Library diversity: Builds one-peptoid-one-bead libraries using 5-mer, 4-mer, and 3-mer peptoid sequences with molecular weights under 1,000 Da
• Targeted molecular recognition: Design focuses on modulating key interactions through side chains, leveraging the absence of backbone hydrogen bond donors
• Validation pipeline: Both computational simulations and experimental validations are employed to identify and confirm peptoid binders
• Biocompatibility advantages: Peptoids are non-immunogenic, highly stable, and capable of crossing the blood-brain barrier

Synthesis efficiency:

• Cost-effective and efficient synthesis enables large-scale library production
• Rich side-chain diversity supports exploration of extensive chemical space
• Peptoids exhibit peptide-like high specificity for molecular recognition

Technology readiness level

This research is at an early-to-mid stage of development. The computational screening methodology and one-bead-one-compound library synthesis represent validated approaches that have demonstrated success in identifying protein binders. Future validation will involve building and screening peptoid libraries using both computationally-guided side chain design and the side-chain similarity approach, followed by experimental confirmation of binding activity. The platform is positioned for collaborative development with industry partners interested in advancing novel molecular binders toward therapeutic applications.