An Improved Method for the Synthesis of Lipopeptide TLR2-Agonists Using Click Chemistry

Wright, Tom H.; Brooks, Anna; Didsbury, Alicia J.; McIntosh, Julie; Burkert, Kristina; Yeung, Ho; Williams, Geoffrey M.; Dunbar, P. Rod; Brimble, Margaret A.

doi:10.1055/s-0033-1339349

Cited by 4 publications

(2 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we provide novel synthetic pathways to synthesize N -acetyl Pam 2 Cys analogs with inexpensive materials and avoiding extra orthogonal protection-deprotection steps. Our bioassay results confirmed that the N-acetyl Pam 2 Cys analogs can effectively activate TLR2/6, which is consistent with previous findings that an extra N-acetyl group did not produce any substantial difference in the ability of an Pam 2 CSK 4 analog to induce CD80 expression [18]. Moreover, our docking results suggest that the extra N-acetyl group can be tolerated during ligand-receptor interactions.…”

Section: Discussionsupporting

confidence: 91%

“…For the receptor-ligand interactions, an X-ray crystal structure of Pam 2 Cys bound to TLR2/TLR6 dimer suggests that the primary amine of the Cys residue does not have a major contribution to the ligand-receptor interactions through any hydrogen bonding interactions [11]. In addition, introducing N-acetylation to Pam 2 Cys analogs was shown to have minimal impact on the compound’s ability to induce immune responses [18].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Development of N-Acetylated Dipalmitoyl-S-Glyceryl Cysteine Analogs as Efficient TLR2/TLR6 Agonists

et al. 2019

View full text Add to dashboard Cite

Cancer vaccine is a promising immunotherapeutic approach to train the immune system with vaccines to recognize and eliminate tumors. Adjuvants are compounds that are necessary in cancer vaccines to mimic an infection process and amplify immune responses. The Toll-like receptor 2 and 6 (TLR2/TLR6) agonist dipalmitoyl-S-glyceryl cysteine (Pam2Cys) was demonstrated as an ideal candidate for synthetic vaccine adjuvants. However, the synthesis of Pam2Cys requires expensive N-protected cysteine as a key reactant, which greatly limits its application as a synthetic vaccine adjuvant in large-scaled studies. Here, we report the development of N-acetylated Pam2Cys analogs as TLR2/TLR6 agonists. Instead of N-protected cysteine, the synthesis utilizes N-acetylcysteine to bring down the synthetic costs. The N-acetylated Pam2Cys analogs were demonstrated to activate TLR2/TLR6 in vitro. Moreover, molecular docking studies were performed to provide insights into the molecular mechanism of how N-acetylated Pam2Cys analogs bind to TLR2/TLR6. Together, these results suggest N-acetylated Pam2Cys analogs as inexpensive and promising synthetic vaccine adjuvants to accelerate the development of cancer vaccines in the future.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Development of N-Acetylated Dipalmitoyl-S-Glyceryl Cysteine Analogs as Efficient TLR2/TLR6 Agonists

et al. 2019

View full text Add to dashboard Cite

show abstract

ChemInform Abstract: An Improved Method for the Synthesis of Lipopeptide TLR2‐Agonists Using Click Chemistry.

et al. 2013

View full text Add to dashboard Cite

Peptide Lipidation – A Synthetic Strategy to Afford Peptide Based Therapeutics

Kowalczyk

Harris

Williams

et al. 2017

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

Peptide and protein aberrant lipidation patterns are often involved in many diseases including cancer and neurological disorders. Peptide lipidation is also a promising strategy to improve pharmacokinetic and pharmacodynamic profiles of peptide-based drugs. Self-adjuvanting peptide-based vaccines commonly utilise the powerful TLR2 agonist PamCys lipid to stimulate adjuvant activity. The chemical synthesis of lipidated peptides can be challenging hence efficient, flexible and straightforward synthetic routes to access homogeneous lipid-tagged peptides are in high demand. A new technique coined Cysteine Lipidation on a Peptide or Amino acid (CLipPA) uses a 'thiol-ene' reaction between a cysteine and a vinyl ester and offers great promise due to its simplicity, functional group compatibility and selectivity. Herein a brief review of various synthetic strategies to access lipidated peptides, focusing on synthetic methods to incorporate a PamCys motif into peptides, is provided.

show abstract

An Improved Method for the Synthesis of Lipopeptide TLR2-Agonists Using Click Chemistry

Cited by 4 publications

References 9 publications

Development of N-Acetylated Dipalmitoyl-S-Glyceryl Cysteine Analogs as Efficient TLR2/TLR6 Agonists

Development of N-Acetylated Dipalmitoyl-S-Glyceryl Cysteine Analogs as Efficient TLR2/TLR6 Agonists

ChemInform Abstract: An Improved Method for the Synthesis of Lipopeptide TLR2‐Agonists Using Click Chemistry.

Peptide Lipidation – A Synthetic Strategy to Afford Peptide Based Therapeutics

Contact Info

Product

Resources

About