Chemical pyrophosphorylation of functionally diverse peptides

Abstract

A highly selective and convenient method for the synthesis of pyrophosphopeptides in solution is reported. The remarkable compatibility with functional groups (alcohol, thiol, amine, carboxylic acid) in the peptide substrates suggests that the intrinsic nucleophilicity of the phosphoserine residue is much higher than previously appreciated. Because the methodology operates in polar solvents, including water, a broad range of pyrophosphopeptides can be accessed. We envision these peptides will find widespread applications in the development of mass spectrometry and antibody-based detection methods for pyrophosphoproteins.

Figure 1

Proteins are pyrophosphorylated by inositol pyrophosphate messengers in the presence of magnesium.

Figure 2. Chemical Pyrophosphorylation and Characterization of Highly Functionalized Nopp140 Peptide Fragment

(a) General reaction scheme to synthesize pyrophosphopeptide 20. (b) Mass spectrometry analysis of 20. (c) ³¹P NMR spectrum of 20.

Scheme 1

Peptide Pyrophosphorylation Using Different Electrophilic Phosphorus Reagents.

Scheme 2. Optimized Method on a Deprotected Peptide