Energy Landscapes of Supramolecular Peptide–Drug Conjugates Directed by Linker Selection and Drug Topology

Abstract

Peptide–drug conjugates that self-assemble into supramolecular nanomaterials have promise for uses in drug delivery. These discrete molecular species offer high and precise drug loading, affording efficient carriers for various therapeutic agents. Their peptide modules, meanwhile, enable biological targeting and stimuli-responsive function while also ordering the assembled nanostructure. The often hydrophobic drug payload likewise acts as a directive for self-assembly in aqueous media. Though accessible synthetic methods have allowed for extensive exploration of the peptide design space, the specific contributions of the drug molecule and its linker to the resulting assembly have been less explored. Hydrophobic drugs frequently have planar domains, conjugated π-systems, and isolated polar groups, which in turn can lead to specific and directional self-interactions. These energies of interaction affect the free energy landscape of self-assembly and may impact the form and assembly process of the desired nanomaterial. Here, two model supramolecular peptide–drug conjugates (sPDCs) are explored, composed of the corticosteroid dexamethasone conjugated to a conserved peptide sequence via two different linker chemistries. The choice of linker, which alters the orientation, rotational freedom, and number of stereoisomers of the prodrug in the final sPDC, impacts the mechanism and energetic barrier of assembly as well as the nano/macroscale properties of the resultant supramolecular materials. Accordingly, this work demonstrates the nonzero energetic contributions of the drug and its linker to sPDC self-assembly, provides a quantitative exploration of the sPDC free energy landscape, and suggests design principles for the enhanced control of sPDC nanomaterials to inform future applications as therapeutic drug carriers.

Lipidation Alters the Structure and Hydration of Myristoylated Intrinsically Disordered Proteins

“…The development of new peptides/proteins has traditionally focused on engineering their amino acid sequence to regulate the structure–function for desired applications, including materials, − vaccines and biopharmaceuticals, − sensors, , and others. − In contrast, nature leverages posttranslational modifications (PTMs)the decoration of proteins with motifs such as phosphate, carbohydrates, and lipids, among othersto modulate protein structure, function, and location with exquisite spatiotemporal control . The chemical diversity of PTMs far surpasses the canonical design space of the 20–22 naturally occurring amino acids, exponentially increasing the diversity of proteinaceous molecules available to regulate the spatiotemporal flow of life-sustaining matter, energy, and information.…”

Fabrication of Enzyme-Responsive Prodrug Self-Assembly Based on Fluazinam for Reducing Toxicity to Aquatic Organisms

“…13,14 The prodrug self-assembly (PDSA) represents an emerging class of drug delivery systems that make prodrugs capable of spontaneously associating into well-defined nanostructures in aqueous solutions through intramolecular forces without the requirement for any harmful additive. 15,16 The PDSA strategy can increase the aqueous solubility and dispersibility of hydrophobic drugs, 17 decrease chemical instability and photodegradation, 18 and minimize the adverse impacts on non-targeted organisms. 19 Recently, the investigation of stimuli-responsive activation mechanisms and designing of the controlled release nanoformulations based on prodrugs have aroused more and more attention and greatly improved the development of PDSA systems.…”

Exploration of the Nucleation Pathway for Supramolecular Fibers

“…The dominant intermolecular forces in these systems, determined by the solvation environment, set the path for a thermodynamically stable or a kinetically trapped intermediate . While filamentous assemblies in solution are frequently driven by hydrogen bonding and amyloid formation, , peptide or polymer-conjugated aromatic molecules suggest another path to one-dimensional fiber formation. − Indeed, peptide-conjugated aromatic molecules possess numerous applications. , Kinetic pathways for fiber formation involve nucleation, elongation, and secondary nucleation . The pathway to metastable aggregates can be further delineated .…”