The design of macromolecular therapeutic constructs for drug discovery or drug delivery requires a firm understanding of the biological system and biological barriers inherent to the system. For example, to ensure precise release of a drug at the desired time and location, precise knowledge of the intracellular kinetics of bond cleavage is required. The kinetics of bond cleavage is dependent not only on the nature of the cleavable bond, but also on the transient composition of the intracellular environment. As such, precise intracellular kinetic measurements and parameters are needed to advance the field and are best acquired with organelle-specific intracellular molecular reporter probes. The development of probes to measure this information in quantitative detail necessitates a proteolytically stable macromolecular platform capable of incorporating a variety of targeting ligands and cleavable bonds in a modular fashion. Similarly, with regards to drug discovery, it is well known that macromolecular sequence is a tight regulator of biological function. As such, the design of any macromolecular drug requires a platform that enables facile manipulation of composition, sequence and structure. Antibiotic drug discovery is one area wherein the massive decline in rate of new antibiotic development can be attributed to difficulties associated with their mode of discovery, structural complexity of natural products, and the ability to access the drug target. Antimicrobial peptides (AMPs), which are small amphiphilic peptides, can overcome these difficulties and have emerged as viable alternatives to conventional antibiotics. However, unlike traditional antibiotics, their potency and promise is attenuated due to their susceptibility to proteolytic degradation, reduced activity in serum and poor toxicology profile. These two highlighted issues in drug delivery and discovery can be addressed with a robust synthetic macromolecular platform that is modular, easy to assemble, scalable and stable to proteases and nucleases.
In an effort to mimic well-behaved biopolymers such as peptides and nucleic acids, we have sought out precise primary sequence control over synthetic oligomers with the goal of creating new biologically active macromolecules. To do this, my lab invented an efficient method for the assembly of synthetic sequence-defined macromolecules called oligothioetheramides (oligoTEAs). As a new structural class, oligoTEAs are uniquely suited for macromolecular drug and probe development due to their rapid synthetic assembly with precise sequence-control, relatively inexpensive production costs, a straightforward two to three-step monomer synthesis, and a massive scope of chemically diverse monomers. Moreover, their abiotic backbone renders them resistant to proteolysis and should result in longer half-lives and greater bioavailability. A unique feature of this oligoTEA platform is that they can be designed to display chemical moieties analogous to bioactive peptide side chains. I will discuss two research projects that leverage the afore-mentioned advantages of oligoTEAs towards discovering new drug types and creating targeted intracellular probes to quantify intracellular bond cleavage kinetics. The precise and modular synthesis of oligoTEAs should allow us to explore the link between molecular composition, sequence and ultimately chemical and biological properties with an eye towards engineering effective and affordable biomolecular therapeutics.
