Folate-targeted verrucarin A reduces the number of activated macrophages in a mouse model of acute peritonitis

Chelvam Venkatesh, Derek D. Doorneweerd, Wei Xia, Karson S. Putt, Philip S. Low

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Activated macrophages contribute prominently to the progression and maintenance of almost all inflammatory and autoimmune diseases. Although non-specific elimination of these phagocytes has been shown to treat animal models of inflammatory disease, the same therapies have been compromised by unacceptable toxicities, because they also kill quiescent macrophages in healthy tissues. In the studies below, we exploit upregulation of folate receptor beta (FRβ) on inflammatory (but not resting) macrophages to target a cytotoxic drug selectively to the inflammatory subset of macrophages. Because many of these activated macrophages are nondividing, we also employ verrucarin A as the cytotoxic payload, since it kills both mitotic and nonmitotic cells by blocking protein synthesis. By inserting a redox-sensitive self-immolative linker between the folate and verrucarin A, we further assure that release of unmodified verrucarin A is triggered primarily after internalization by an FRβ-positive cell. The resulting folate-verrucarin A conjugate is shown to kill FR-expressing cells in vitro in a manner that can be inhibited by competition with 100-fold excess folic acid. The folate-verrucarin A conjugate is also shown to successfully treat a murine model of inflammatory peritonitis by eliminating inflammatory macrophages without killing other cells in the same peritonitis fluid. Based on this high specificity for inflammatory macrophages, we conclude that folate-verrucarin A warrants continued exploration as a potential therapy for inflammatory and autoimmune diseases in humans.

Original languageEnglish (US)
Article number128091
Pages (from-to)128091
JournalBioorganic and Medicinal Chemistry Letters
StatePublished - Jun 15 2021


  • Autoimmune disease
  • Folate
  • Folate targeting
  • Inflammatory disease
  • Verrucarin A
  • Trichothecenes/chemistry
  • Peritonitis/drug therapy
  • Folic Acid/chemistry
  • Structure-Activity Relationship
  • Dose-Response Relationship, Drug
  • Macrophages/drug effects
  • Animals
  • Mice
  • Molecular Structure
  • Disease Models, Animal
  • Folate Receptor 2/metabolism

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmaceutical Science
  • Organic Chemistry


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