title: Identification of Adjuvantic Activity of Amphotericin B in a Novel, Multiplexed, Poly-TLR/NLR High-Throughput Screen.
abstract: Small-molecule agonists have been identified for TLR7, TLR8, TLR4 and TLR2 thus far, and chemotypes other than those of canonical ligands are yet to be explored for a number of innate immune receptors. The discovery of novel immunostimulatory molecules would enhance the repertoire of tools available for interrogating innate immune effector mechanisms, and provide additional venues for vaccine adjuvant development. A multiplexed, reporter gene-based high-throughput assay capable of detecting agonists of TLR2, TLR3, TLR4, TLR5, TLR7, TLR8, TLR9, NOD1 and NOD2 was utilized in screening 123,943 compounds, in which amphotericin B (AmpB) and nystatin were identified as prominent hits. The polyene antifungal agents act as TLR2- and TLR4-agonists. The TLR4-stimulatory activity of AmpB was similar to that of monophosphoryl lipid A, suggestive of TRIF-biased signaling. The adjuvantic activity of AmpB, at a dose of 100 micrograms, was comparable to several other candidate adjuvants in rabbit models of immunization. These results point to its potential applicability as a safe and effective adjuvant for human vaccines.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, United States of America.|Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Alex C D
authors.initials: AC
authors.lastname: Salyer
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, United States of America.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caruso
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, United States of America.
authors.forename: Karishma K
authors.initials: KK
authors.lastname: Khetani
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, United States of America.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Fox
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, United States of America.
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.affiliation: Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, United States of America.
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000666:Amphotericin B / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D009761:Nystatin / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000819:agonists*; D051193:Toll-Like Receptors / Q000819:agonists*; D014612:Vaccines
chemical_list: D000276:Adjuvants, Immunologic; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D014612:Vaccines; D009761:Nystatin; D000666:Amphotericin B