The research objective of this Partnerships for Innovation (PFI) project is to gain the knowledge needed to overcome the technical hurdles for the synthesis of polyethylene glycols (PEGs). Among many of the technical discoveries during the course of the project, a protecting group that is seemingly unsuitable for PEG synthesis has been found to be suitable for the purpose. This protecting group is called base-labile protecting group, which means it can be removed with a base after it finishes its protection task. Protecting groups previously used for PEG synthesis are all non-base-labile, and they are removed by reagents that are not basic.  Using the base-labile protecting group, PEG synthesis routes can be as much as 30% shorter, which significantly lowers materials and labor for PEG synthesis. The base-labile protecting group also makes the synthesis more efficient, which means less reaction time, less amount of reagent, and higher yield of product. Another important discovery of the project is the feasibility of automation of the process of PEG synthesis. The PEG intermediates and products are anchored onto an insoluble solid support,  and reagents for the PEG synthesis are delivered to a reaction vessel sequentially by a modified peptide synthesizer controlled by a computer. After a reaction is complete, excess reagents and side products are washed away, also under control by the computer. The PEG intermediate or product on the insoluble solid support remains in the reaction vessel, waiting for the reaction of the next step to take place. The process continues automatically until the reactions of all steps required for the PEG synthesis are accomplished. The entire, otherwise complicated and highly labor intensive, process does not require any human manipulation once the synthesis is initiated. The major advantage of the automated PEG synthesis is the reduction of labor. Other advantages include saving materials for the synthesis and potentially more pure products. The above two discoveries, base-labile protecting group and automated PEG synthesis, along with other technical discoveries such as suitable reagents and solvents, appropriate washing schemes, and tactics for preventing side reactions have been integrated to give an efficient automated PEG synthesis technology, which has all the advantages described above for the discoveries. Using the integrated technology, the synthesis of several PEG derivatives with close to 100% yield and purity has been demonstrated.

The discoveries have the potential to make PEGs including their derivatives much cheaper. PEGs have wide applications including nanomedicine (e.g. COVID-19 mRNA vaccine), drug PEGylation (e.g. delivery of protein and gene based drugs), and bioconjugation. Lowering the cost of PEGs can lower the production costs of many medicines and other materials. While carrying out this PFI project, two PhD students received training in organic synthesis and automated solid phase synthesis. One of them has graduated, and is now an employee of a Fortune 500 company in the US doing work related to automated synthesis. Earlier, another PhD student also received training from the project. He underwent the intensive NSF I-Corps training related to this project. He is now an employee of a startup company in the US that is backed up by several Fortune 500 companies. His work in the company is also related to automated synthesis. In addition, one MS student and two undergraduate students also received training in organic synthesis via this PFI project. Among the trainees, one PhD student and one undergraduate student are female students. The trainees of this PFI project are or will be part of the workforce that makes the US competitive in science and technology in the world. 

Last Modified: 11/26/2022
Modified by: Shiyue Fang