Accelerated NLRP3 inflammasome-inhibitory peptide design using a recurrent neural network model and molecular dynamics simulations

Anomalous NLRP3 inflammasome responses have been linked to multiple health issues, including but not limited to atherosclerosis, diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disease. Thus, targeting NLRP3 and modulating its associated immune response might be a promising strategy for developing new anti-inflammatory drugs. Herein, we report a computational method for de novo peptide design for targeting NLRP3 inflammasomes. The described method leverages a long-short-term memory (LSTM) network based on a recurrent neural network (RNN) to model a valuable latent space of molecules. The resulting classifiers are utilized to guide the selection of molecules generated by the model based on circular dichroism spectra and physicochemical features derived from high-throughput molecular dynamics simulations. Of the experimentally tested sequences, 60% of the peptides showed NLRP3-mediated inhibition of IL-1β and IL-18. One peptide displayed high potency against NLRP3-mediated IL-1β inhibition. However, NLRC4 and AIM2 inflammasome-mediated IL-1β secretion was uninterrupted by this peptide, demonstrating its selectivity toward the NLRP3 inflammasome. Overall, these results indicate that deep learning and molecular dynamics can accelerate the discovery of NLRP3 inhibitors with potent and selective activity

A Novel Small-Molecule Inhibitor of Endosomal TLRs Reduces Inflammation and Alleviates Autoimmune Disease Symptoms in Murine Models

Toll-like receptors (TLRs) play a fundamental role in the inflammatory response against invading pathogens. However, the dysregulation of TLR-signaling pathways is implicated in several autoimmune/inflammatory diseases. Here, we show that a novel small molecule TLR-inhibitor (TAC5) and its derivatives TAC5-a, TAC5-c, TAC5-d, and TAC5-e predominantly antagonized poly(I:C) (TLR3)-, imiquimod (TLR7)-, TL8-506 (TLR8)-, and CpG-oligodeoxynucleotide (TLR9)-induced signaling pathways. TAC5 and TAC5-a significantly hindered the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), reduced the phosphorylation of mitogen-activated protein kinases, and inhibited the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6. Besides, TAC5-a prevented the progression of psoriasis and systemic lupus erythematosus (SLE) in mice. Interestingly, TAC5 and TAC5-a did not affect Pam3CSK4 (TLR1/2)-, FSL-1 (TLR2/6)-, or lipopolysaccharide (TLR4)-induced TNF-α secretion, indicating their specificity towards endosomal TLRs (TLR3/7/8/9). Collectively, our data suggest that the TAC5 series of compounds are potential candidates for treating autoimmune diseases such as psoriasis or SLE