Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids

M. P. Lutolf, N. Tirelli, S. Cerritelli, L. Cavalli, J. A. Hubbell

Research output: Contribution to journalArticle

283 Citations (Scopus)

Abstract

A quantitativestructure - reactivity relationship for the Michael-type addition of thiols onto acrylates was determined. Several thiol-containing peptides were investigated by examining the correlation between the second-order rate constant of their addition onto PEG-diacrylate and the pKa of the thiols within a peptide. By introducing charged amino acids in close proximity to a cysteine, the pKa of the thiol was systematically modulated by electrostatic interactions. Positive charges from the amino acid arginine decreased the pKa of the thiol and accelerated the reaction with acrylates while negative charges from aspartic acids showed the opposite effect. A linear correlation between thiolate concentrations and kinetic constants was found, confirming the role of thiolates as the reactive species in this Michael-type reaction. The relevant factors influencing the reactivity were the sign and the number of the neighboring charges, while the position of these charges had little effect on reactivity. These results provide a basis for the rational design of peptides, where the kinetics and thus selectivity of protein/peptide conjugation with polymeric structures via Michael-type addition reactions can be controlled.

Original languageEnglish
Pages (from-to)1051-1056
Number of pages6
JournalBioconjugate Chemistry
Volume12
Issue number6
DOIs
StatePublished - Dec 27 2001
Externally publishedYes

Fingerprint

Sulfhydryl Compounds
Peptides
Amino acids
Modulation
Amino Acids
Acrylates
Arginine
Addition reactions
Kinetics
Coulomb interactions
Polyethylene glycols
Rate constants
Static Electricity
Aspartic Acid
Cysteine
Proteins
Acids

ASJC Scopus subject areas

  • Chemistry(all)
  • Organic Chemistry
  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry

Cite this

Lutolf, M. P., Tirelli, N., Cerritelli, S., Cavalli, L., & Hubbell, J. A. (2001). Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids. Bioconjugate Chemistry, 12(6), 1051-1056. https://doi.org/10.1021/bc015519e

Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids. / Lutolf, M. P.; Tirelli, N.; Cerritelli, S.; Cavalli, L.; Hubbell, J. A.

In: Bioconjugate Chemistry, Vol. 12, No. 6, 27.12.2001, p. 1051-1056.

Research output: Contribution to journalArticle

Lutolf, MP, Tirelli, N, Cerritelli, S, Cavalli, L & Hubbell, JA 2001, 'Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids', Bioconjugate Chemistry, vol. 12, no. 6, pp. 1051-1056. https://doi.org/10.1021/bc015519e
Lutolf, M. P. ; Tirelli, N. ; Cerritelli, S. ; Cavalli, L. ; Hubbell, J. A. / Systematic modulation of Michael-type reactivity of thiols through the use of charged amino acids. In: Bioconjugate Chemistry. 2001 ; Vol. 12, No. 6. pp. 1051-1056.
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