Synthesis of Cyclic Megamolecules

J Am Chem Soc. 2018 May 23;140(20):6391-6399. doi: 10.1021/jacs.8b02665. Epub 2018 May 15.

Abstract

This paper describes the synthesis of giant cyclic molecules having diameters of 10-20 nm. The molecules are prepared through the reactions of a fusion protein building block with small molecule linkers that are terminated in irreversible inhibitors of enzyme domains present in the fusion. This building block has N-terminal cutinase and C-terminal SnapTag domains that react irreversibly with p-nitrophenyl phosphonate (pNPP) and benzylguanine (BG) groups, respectively. We use a bis-BG and a BG-pNPP linker to join these fusion proteins into linear structures that can then react with a bis-pNPP linker that joins the ends into a cyclic product. The last step can occur intramolecularly, to give the macrocycle, or intermolecularly with another equivalent of linker, to give a linear product. Because these are coupled first- and second-order processes, an analysis of product yields from reactions performed at a range of linker concentrations gives rate constants for cyclization. We determined these to be 9.7 × 10-3 s-1, 2.3 × 10-3 s-1, and 8.1 × 10-4 s-1 for the dimer, tetramer, and hexamer, respectively. This work demonstrates an efficient route to cyclic macromolecules having nanoscale dimensions and provides new scaffolds that can be generated using the megamolecule approach.

Publication types

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

MeSH terms

  • Carboxylic Ester Hydrolases / chemical synthesis
  • Carboxylic Ester Hydrolases / chemistry*
  • Cross-Linking Reagents / chemical synthesis
  • Cross-Linking Reagents / chemistry
  • Cyclization
  • Guanine / analogs & derivatives*
  • Guanine / chemical synthesis
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry*
  • Models, Molecular
  • Nitrophenols / chemical synthesis
  • Nitrophenols / chemistry*
  • O(6)-Methylguanine-DNA Methyltransferase / chemical synthesis
  • O(6)-Methylguanine-DNA Methyltransferase / chemistry*
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry*
  • Protein Domains
  • Protein Multimerization

Substances

  • Cross-Linking Reagents
  • Macrocyclic Compounds
  • Nitrophenols
  • Organophosphonates
  • 4-nitrophenyl phosphonate
  • Guanine
  • O(6)-Methylguanine-DNA Methyltransferase
  • Carboxylic Ester Hydrolases
  • cutinase