Collaborative Research: Protein-Like Polymers: Theory and Design for Engaging Biological Interfaces

Northwestern University, Evanston IL

Investigators

Abstract

Non-Technical Description We have developed a new kind of material that provides a way to mimic proteins. Proteins are the key drivers of cellular processes and are critical for specific function and are implicated in specific diseases. We call these materials Protein-like Polymers (PLPs). PLPs are proteomimetic and enable rapid and scalable emulation of protein behaviors. PLPs are exceptional at entering cells where they can be used to study cellular processes. The focus of this work is to elucidate how this occurs and the mechanism by which PLPs interact with biological membranes and compartments and in turn how they enter cells. These features of PLPs lend them to serving as reagents for the detection of proteins of interest, as probes and as intracellular binders of proteins. Critically, these are features not easily accessible to small molecules or antibodies, both of which make up the vast majority of compounds currently used in this area. This means that PLPs have the potential to be developed as unique modulators of cellular function. With a platform technology in hand for stabilizing peptides, increasing their binding and penetrating cells, we propose a fundamental set of studies to elucidate these properties and how they relate to PLP structure both in solution and at cell membranes. We will study the effect of chemical structure on their performance and determine critical parameters that govern their behavior in biological systems. Technical Description The proposed studies develop and investigate Protein-Like Polymers (PLPs). PLPs are large, flexible proteomimetic macromolecules that resemble proteins in form and function. The size and multivalency provide a basis for the development of drugs that can engage the “undruggable” large, flat, featureless interfaces where small molecules have traditionally struggled and that antibodies cannot access (i.e. intracellular targets). We propose that the PLPs access cells and engage membranes in analogy to the permeability enabled by the kind of flexibility and chameleonic behavior exhibited by cyclosporin A (CsA). Indeed, this kind of environment-adaptive behavior wherein molecules can be dissolved in aqueous solution, and also reside within lipophilic environments, is increasingly desirable. The PLP is inherently metaphilic (transiently amphiphilic) with a core polymer scaffold of tunable rigidity and lipophilicity and hydrophilic peptide side chains as brushes, capable of introducing positive charge and ultimately protein recognition function. In the proposed work, we aim to study aqueous phase conformations and to map these onto behavior at lipid membranes and ultimately within cells using advanced methods and a set of newly synthesized PLPs. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.