Programming Supramolecular Biohybrids as Precision Therapeutics

Abstract

CONSPECTUS: Chemical programming of macromolecular structures to instill a set of defined chemical properties designed to behave in a sequential and precise manner is a characteristic vision for creating next generation nanomaterials. In this context, biopolymers such as proteins and nucleic acids provide an attractive platform for the integration of complex chemical design due to their sequence specificity and geometric definition, which allows accurate translation of chemical functionalities to biological activity. Coupled with the advent of amino acid specific modification techniques, "programmable" areas of a protein chain become exclusively available for any synthetic customization. We envision that chemically reprogrammed hybrid proteins will bridge the vital link to overcome the limitations of synthetic and biological materials, providing a unique strategy for tailoring precision therapeutics. In this Account, we present our work toward the chemical design of protein- derived hybrid polymers and their supramolecular responsiveness, while summarizing their impact and the advancement in biomedicine. Proteins, in their native form, represent the central framework of all biological processes and are an unrivaled class of macromolecular drugs with immense specificity. Nonetheless, the route of administration of protein therapeutics is often vastly different from Nature's biosynthesis. Therefore, it is imperative to chemically reprogram these biopolymers to direct their entry and activity toward the designated target. As a consequence of the innate structural regularity of proteins, we show that supramolecular interactions facilitated by stimulus responsive chemistry can be intricately designed as a powerful tool to customize their functions, stability, activity profiles, and transportation capabilities. From another perspective, a protein in its denatured, unfolded form serves as a monodispersed, biodegradable polymer scaffold decorated with functional side chains available for grafting with molecules of interest. Additionally, we are equipped with analytical tools to map the fingerprint of the protein chain, directly elucidating the structure at the molecular level. Contrary to conventional polymers, these biopolymers facilitate a more systematic avenue to investigate engineered macromolecules, with greater detail and accuracy. In this regard, we focus on denaturing serum albumin, an abundant blood protein, and exploit its peptidic array of functionalities to program supramolecular architectures for bioimaging, drug and gene delivery. Ultimately, we seek to assimilate the evolutionary advantage of these protein based biopolymers with the limitless versatility of synthetic chemistry to merge the best of both worlds.

Site‐Selective Disulfide Modification of Proteins: Expanding Diversity beyond the Proteome

“…Proteins play a significant role in biological functions and are one of the most versatile building blocks in biology due to their diverse structural and functional properties . Due to their unique bioactivities and high biocompatibility, the therapeutic usage of proteins is emerging . However, protein therapeutics also have some inherent drawbacks such as poor stability, sometimes high immunogenicity and antigenicity or low blood circulation times .…”

“…2016, 22, 17112 -17129 www.chemeurj.org their unique bioactivities and high biocompatibility, the therapeutic usage of proteins is emerging. [99,100] However, protein therapeutics also have some inherent drawbacks such as poor stability, sometimes high immunogenicity and antigenicity or low blood circulation times. [101,102] PEGylation of proteins represents a common strategy where the polymers are adopted as high-molecular-weight substituents to enhance pharmacokinetic parameters and promote accumulation of the proteins in tumour tissue.…”

Rationally Designed Supramolecular Organic Hosts for Benzo[a]pyrene Binding and Detection

“…[16] Synthesis of 15b: Compound 15b was synthesized according to our previously reported procedures. 1 13 : Macrocycles 1-4 were synthesized according to our previously reported procedures. was dissolved in anhydrous toluene (30 mL), [3-(hydroxymethyl)phenyl]boronic acid (compound 16) (654 mg, 4.307 mmol, 2.3 equiv.)…”

“…was dissolved in anhydrous ethanol (16 mL), and sodium carbonate (1.984 g, 18.726 mmol, 10 equiv.) 1 13 The aqueous sodium carbonate solution was degassed under nitrogen for 30-60 min.…”

“…[12] Despite the long history of supramolecular chemistry in general, and synthetic macrocycles in particular, little research has been done towards developing rational structure-property relationships between subtle structural variations in the supramolecular hosts and the ability of these hosts to engage in the requisite intermolecular interactions. [13] Despite the fact that structural variations of several types "should" affect supramolecular forces, the nature of these effects is difficult to predict, and recent examples from polymer chemistry have highlighted the extent to 6194 significant differences in their ability to promote non-covalent energy transfer from benzo[a]pyrene to a BODIPY fluorophore, with energy transfer efficiencies ranging from 32 % to 398 %. These differences can be explained using a variety of computational investigative techniques, which highlight the flexibility of the macrocycle architectures to accommodate benzo[a]pyrene and to promote close donor-acceptor interactions.…”