Structure-activity relationship studies in substituted sulfamoyl benzamidothiazoles that prolong NF-κB activation. (1st August 2021)

• Record Type: Journal Article
• Authors: Shukla, Nikunj M.; Chan, Michael; Lao, Fitzgerald S.; Chu, Paul J.; Belsuzarri, Masiel; Yao, Shiyin; Nan, Jason; Sato-Kaneko, Fumi; Saito, Tetsuya; Hayashi, Tomoko; Corr, Maripat; Carson, Dennis A.; Cottam, Howard B.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 43(2021)
• Publication Date: 2021-08-01
• Subjects: Adjuvant -- NF-κB -- LPS -- Toll-like receptor -- Vaccine -- Immunization -- MPLA -- Thiazoles -- Affinity probe; ANOVA Analysis of variance -- APC antigen presenting cells -- AS04 Adjuvant System 04 -- BMDCs bone marrow-derived dendritic cells -- DIPEA N, N-diisopropylethylamine -- DMF N, N-dimethylformamide -- DMSO dimethyl sulfoxide -- EC50 half maximal effective concentration -- ELISA enzyme-linked immunosorbent assay -- FBS fetal bovine serum -- FDA Food and Drug Administration -- FRET Förster resonance energy transfer -- HATU (1-[bis(dimethylamino)methylene]-1H-1, 2, 3-triazolo[4, 5-b]pyridinium 3-oxide hexafluorophosphate -- HRMS high resolution mass spectrometry -- HTS high-throughput screening -- IFN interferon -- Ig immunoglobulin -- IL interleukin -- IRAK-M interleukin-1 receptor-associated kinase-M -- LC-MS liquid chromatography-mass spectrometry -- LPS lipopolysaccharide -- m meta -- MPLA monophosphoryl Lipid A -- MTT (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl tetrazolium bromide) -- NF-κB nuclear factor kappa B -- NLR nucleotide-binding oligomerization domain-like receptors (NLRs) -- o ortho -- OD optical density -- OVA ovalbumin -- p para -- PRR pattern recognition receptors -- RLR RIG-I-like receptors -- SAR structure–activity relationship -- SEAP secreted embryonic alkaline phosphatase -- THF tetrahydrofuran -- TLC thin layer chromatography -- TLR Toll-like receptor -- TNF tumor necrosis factor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116242
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: In the face of emerging infectious diseases, there remains an unmet need for vaccine development where adjuvants that enhance immune responses to pathogenic antigens are highly desired. Using high-throughput screens with a cell-based nuclear factor κB (NF-κB) reporter assay, we identified a sulfamoyl benzamidothiazole bearing compound 1 that demonstrated a sustained activation of NF-κB after a primary stimulus with a Toll-like receptor (TLR)-4 agonist, lipopolysaccharide (LPS). Here, we explore systematic structure–activity relationship (SAR) studies on compound 1 that indicated the sites on the scaffold that tolerated modification and yielded more potent compounds compared to 1 . The selected analogs enhanced release of immunostimulatory cytokines in the human monocytic cell line THP-1 cells and murine primary dendritic cells. In murine vaccination studies, select compounds were used as co-adjuvants in combination with the Food and Drug Administration approved TLR-4 agonistic adjuvant, monophosphoryl lipid A (MPLA) that showed significant enhancement in antigen-specific antibody titers compared to MPLA alone. Additionally, our SAR studies led to identification of a photoaffinity probe which will aid the target identification and mechanism of action studies in the future.