Structure based design, synthesis and identification of novel covalent reversible dual TLR2/TLR9 small molecule...

Area of Science:

• Immunology
• Neuroscience
• Oncology

Background:

• Inflammation is a critical factor in neurodegenerative diseases (e.g., Parkinson's Disease, ALS) and cancers (e.g., pancreatic cancer, glioblastoma).
• Toll-like receptors (TLRs), specifically TLR2 and TLR9, are key mediators of inflammatory responses in both the central nervous system (CNS) and periphery.
• Activation of TLR2 and TLR9 contributes to disease pathogenesis, with their inactivation showing therapeutic benefits in preclinical models.

Purpose of the Study:

• To identify and develop novel therapeutic agents targeting TLR2 and TLR9 for the treatment of inflammatory CNS diseases and malignancies.
• To design and synthesize a new class of dual TLR2/9 antagonists based on a key binding locus in the TLR2/9 TIR domain.

Main Methods:

• Utilized a key binding locus in the TLR2/9 TIR domain to guide the design of reversible covalent drugs (RCDs).
• Synthesized a novel series of dual TLR2/9 antagonists.
• Assessed the potency and specificity of the antagonists in inhibiting TLR2 and TLR9 signaling using specific agonists.
• Evaluated in-vitro ADME (Absorption, Distribution, Metabolism, and Excretion) and safety profiles of the antagonist analogs.

Main Results:

• Identified a critical binding locus in the TLR2/9 TIR domain, enabling the design of dual antagonists.
• Developed a novel series of dual TLR2/9 antagonists with sub-micromolar inhibitory concentrations against TLR2 and TLR9 signaling.
• Demonstrated that the antagonists selectively inhibited TLR2 and TLR9 without activating other TLRs.
• Observed favorable in-vitro ADME and safety profiles for the developed antagonist analogs.

Conclusions:

• Dual TLR2/9 antagonism represents a potentially viable therapeutic strategy for diseases driven by inflammation.
• The novel series of dual TLR2/9 antagonists described herein show promise for treating neurodegenerative disorders and cancers with inflammatory components.
• Further development of these antagonists could lead to effective treatments for a range of debilitating diseases.