Sequence-Defined Oligomers from Hydroxyproline Building Blocks for Parallel Synthesis Applications

Rosemary L Kanasty; Arturo J Vegas; Luke M Ceo; Martin Maier; Klaus Charisse; Jayaprakash K Nair; Robert Langer; Daniel G Anderson

doi:10.1002/anie.201602748

Sequence-Defined Oligomers from Hydroxyproline Building Blocks for Parallel Synthesis Applications

Angew Chem Int Ed Engl. 2016 Aug 8;55(33):9529-33. doi: 10.1002/anie.201602748. Epub 2016 Jul 1.

Authors

Rosemary L Kanasty^{1

2}, Arturo J Vegas^{2

3

4}, Luke M Ceo^{2

3

4}, Martin Maier⁵, Klaus Charisse⁵, Jayaprakash K Nair⁵, Robert Langer^{1

2

3

6

7

8}, Daniel G Anderson^{9

10

11

12

13

14}

Affiliations

¹ Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main St., Cambridge, MA, 02142, USA.
³ Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA.
⁴ Department of Chemistry, Boston University, 590 Commonwealth Avenue, Boston, MA, 02215, USA.
⁵ Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA, 02142, USA.
⁶ Division of Health Science Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
⁷ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
⁸ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA.
⁹ Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. dgander@mit.edu.
¹⁰ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main St., Cambridge, MA, 02142, USA. dgander@mit.edu.
¹¹ Department of Anesthesiology, Boston Children's Hospital, 300 Longwood Ave, Boston, MA, 02115, USA. dgander@mit.edu.
¹² Division of Health Science Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. dgander@mit.edu.
¹³ Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. dgander@mit.edu.
¹⁴ Harvard-MIT Division of Health Science and Technology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, 02139, USA. dgander@mit.edu.

Abstract

The functionality of natural biopolymers has inspired significant effort to develop sequence-defined synthetic polymers for applications including molecular recognition, self-assembly, and catalysis. Conjugation of synthetic materials to biomacromolecules has played an increasingly important role in drug delivery and biomaterials. We developed a controlled synthesis of novel oligomers from hydroxyproline-based building blocks and conjugated these materials to siRNA. Hydroxyproline-based monomers enable the incorporation of broad structural diversity into defined polymer chains. Using a perfluorocarbon purification handle, we were able to purify diverse oligomers through a single solid-phase extraction method. The efficiency of synthesis was demonstrated by building 14 unique trimers and 4 hexamers from 6 diverse building blocks. We then adapted this method to the parallel synthesis of hundreds of materials in 96-well plates. This strategy provides a platform for the screening of libraries of modified biomolecules.

Keywords: bioconjugates; fluorous synthesis; oligomers; sequence-defined polymers; siRNA.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Hydroxyproline / chemistry*
Molecular Structure
Polyurethanes / chemical synthesis*
Polyurethanes / chemistry
Solid Phase Extraction

Substances

Polyurethanes
Hydroxyproline

Abstract

Publication types

MeSH terms

Substances

Grants and funding