A Small Molecule Selected from a DNA‐Encoded Library of Natural Products That Binds to TNF‐α and Attenuates Inflammation In Vivo

Abstract

Tumor necrosis factor 𝜶 (TNF-𝜶) inhibitors have shown great success in the treatment of autoimmune diseases. However, to date, approved drugs targeting TNF-𝜶 are restricted to biological macromolecules, largely due to the difficulties in using small molecules for pharmaceutical intervention of protein-protein interactions. Herein the power of a natural product-enriched DNA-encoded library (nDEL) is exploited to identify small molecules that interfere with the protein-protein interaction between TNF-𝜶 and the cognate receptor. Initially, to select molecules capable of binding to TNF-𝜶 , "late-stage" DNA modification method is applied to construct an nDEL library consisted of 400 sterically diverse natural products and pharmaceutically active chemicals. Several natural products, including kaempferol, identified not only show direct interaction with TNF-𝜶, but also lead to the blockage of TNF-𝜶/TNFR1 interaction. Significantly, kaempferol attenuates the TNF-𝜶 signaling in cells and reduces the 12-O-tetradecanoylphorbol-13acetateinduced ear inflammation in mice. Structure-activity-relationship analyses demonstrate the importance of substitution groups at C-3, C-7, and C-4' of kaempferol. The nDEL hit, kaempferol, represents a novel chemical scaffold capable of specifically recognizing TNF-𝜶 and blocking its signal transduction, a promising starting point for the development of a small molecule TNF-𝜶 inhibitor for use in the clinical setting.

Metal‐Free and Open‐Air Arylation Reactions of Diaryliodonium Salts for DNA‐Encoded Library Synthesis

“…A large number of hits have been identified from DEL for various disease targets as well as for chemical probes. [4][5][6] Notably, some drug candidates originated from DEL hits have already entered into clinical testing for various diseases. [7] Nowadays, DEL is becoming an indispensable technology for hit discovery campaigns either in big pharmaceutical companies or academic laboratories.…”

“…[69] We envisaged that the weakly acidic properties of phenols (pKa ≈ 9.94) could make them readily dissociate into anionic forms of ArO − under weakly basic conditions, thus offering an opportunity for them to outcompete the DNA bases and amide competitors when combined with DAIs. Taking these observations into account and to continue our ongoing effort in DEL synthesis and selection, [5,34] we reported herein the address of the sluggish issue of the arylation of DNA-conjugated phenolic compounds via a substrate activation strategy (umpolung). We employed the highly electrophilic and reactive DAIs as Ar + sources to replace Ar-X (X = halogen, OTf, OFs, activated by metal to form Ar-M-X, Ar − ) in cross-coupling, thus converting the conventional cross-coupling pathway into concerted nucleophilic aromatic substitution (CS N Ar) pathway (Figure 1C), [69] and, at the same time, obviates the need to activate the aromatic ring by using highly electron-withdrawing substituents such as those in traditional S N Ar reactions.…”

An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis

“…In silico tools were also used to identify plant-derived natural products that prevent the formation of TNF trimers ( Papadopoulou et al, 2021 ). By applying virtual screening technology based on SPD-304, new inhibitors of the TNF-TNFR1 interaction have been identified ( Sun et al, 2020 ) and recently, SPD-304 was used as a tool to discover molecules such as kaempferol from a natural product enriched DNA-encoded library (nDEL) ( Wang et al, 2022 ).…”

Recent Advances in ROS-Scavenging Metallic Nanozymes for Anti-Inflammatory Diseases: A Review

“… 23 24 Recently, anti-leukotrienes, which hinder inflammatory cell recruitment to inflammatory sites, and proinflammatory cytokine inhibitors such as anti-TNF α and anti- IL-1 antibodies have emerged. 25 26 27 28 29 30 31 However, these treatments are inadequate for controlling the progression of complex inflammation. Therefore, the development of novel anti-inflammatory approaches to overcome these limitations with adequate efficacy is crucial.…”