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Synthesis and Evaluation of Novel TLR2 Agonists as Potential Adjuvants for Cancer Vaccines

Benjamin L Lu1,2, Geoffrey M Williams3,2, Daniel J Verdon3,2

  • 1School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand.

Journal of Medicinal Chemistry
|August 17, 2019
PubMed

Insights

Toll-like receptor 2 (TLR2) agonists, like Pam2Cys, are promising cancer immunotherapies. Modifying their structure, particularly using the R diastereomer and homologation, can enhance their potency for activating the immune system against tumors.

Area of Science:

  • Immunology
  • Medicinal Chemistry
  • Oncology

Background:

  • Cancer immunotherapy offers a targeted approach with fewer side effects than traditional treatments.
  • Toll-like receptor 2 (TLR2) agonists, specifically lipopeptides with the Pam2Cys motif, are potent immunostimulants.
  • These agonists act as danger signals to activate the immune system against tumor antigens, making them attractive for cancer treatment development.

Purpose of the Study:

  • To investigate the structure-activity relationship (SAR) of Pam2Cys-conjugated lipopeptides for TLR2 activation.
  • To explore the impact of stereochemistry, N-terminal acylation, and ester linkage homologation on TLR2 agonist activity.

Main Methods:

  • Synthesized and tested various Pam2Cys analogues with modifications in stereochemistry, N-terminal acylation, and linker length.
  • Evaluated the TLR2 activity of these modified lipopeptides.

Main Results:

  • The R diastereomer of Pam2Cys is significantly more potent than the S diastereomer.
  • N-terminal acylation generally reduces TLR2 activity.
  • Homologation of the ester functionalities yielded analogues with activity comparable to native Pam2Cys.

Conclusions:

  • Stereochemistry is critical for TLR2 agonist activity, with the R configuration being superior.
  • Structural modifications, particularly homologation, can lead to potent TLR2 agonists for cancer immunotherapy.
  • These findings provide valuable insights for designing novel and effective cancer immunotherapeutic agents.

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