Thermodynamic and Kinetic Considerations in the Rational Design of Supramolecular Peptide-Drug Conjugates

Supramolecular chemistry is the chemistry of life. Each day the four major classes of biomolecules that compose every living organism engage in an intricate dance of recognition, coalescence, and dissociation driven by the energetic sums of hundreds of non-covalent chemical interactions. Even enzymes, the biochemical foundries and immolators of covalent bonds, first capture their targets through supramolecular recognition. With this view of the living world, a powerful opportunity arises to intervene in life’s problems using life’s tools. In an array of diseases and dysfunctions, biomaterials leveraging supramolecular construction and functionality can interface with tissues, responding to disease indicators quickly and with fidelity inspired by the living system itself. Of widely studied supramolecular materials, synthetic peptide self-assemblies offer distinct advantages in therapeutic delivery. Leveraging the same secondary structures which order and stabilize natural proteins, peptide self-assemblies can be designed to form nanomaterials with precise form factors that are encoded via the peptide amino acid sequence. Robust and accessible synthetic methods allow for the inclusion of bioactive domains and biologically sensitive covalent and noncovalent chemistries, and the natural composition of the materials generally leads to excellent biocompatibility and degradability.

Herein, I first provide an introduction which surveys the design and use of peptide self-assemblies as therapeutic carriers, including the major design motifs, their capacity to deliver a broad range of therapeutics, and their ability to perform bio responsive functions which enhance the quality of the therapy. I then focus on a class of self-assemblies I term supramolecular peptide-drug conjugates (sPDCs) which are the primary subject of my research. sPDCs tether small molecule drugs to self-assembling peptides, often through biologically labile prodrug chemistries. In this way the drug directly participates in the supramolecular chemistry controlling the emergence and form of the assembly, yielding nanomaterials which are composed of a single, well-defined molecule and have high and precise drug loading. While decades of experimentation have extensively explored the design space of self-assembling peptides, sPDCs are a more recent paradigm, and the specific contributions of the prodrug supramolecular chemistry to the energetics of these systems are less understood. Accordingly, I prepared two model sPDCs which tethered the anti-inflammatory drug dexamethasone to a preserved peptide sequence via either ester or hydrazone prodrug chemistries. The resulting materials were characterized at the molecular scale, nanoscale, and macroscale to elucidate the non-zero energetic contributions of the prodrug domain to the thermodynamics of the assembly process and performance of the resultant materials. Moving on, I produced a new generation of sPDC designs which alleviate some thermodynamic constraints of the original model systems, allowing for more precise control of the emergent material properties via the encoded peptide sequence. It is my belief that this work will accelerate the development of sPDCs which are tunable towards specific therapeutic applications and have modular drug cargo capacities. Finally, I conclude with my views on what work is necessary to accelerate the development of sPDCs in clinical applications, which will involve collaborative efforts between researchers in wet labs, molecular simulation, and machine learning.