Prof. Dr. Günther Weindl
Freie Universität Berlin, Germany
Freie Universität Berlin, Institute of Pharmacy (Pharmacology and Toxicology),
Königin-Luise-Straße 2+4, 14195 Berlin, Germany
Pharmacological Targeting of The First Barrier of The Immune Response
The family of Toll-like receptors (TLRs) belong to the most prominent group of pattern recognition receptors that form the first barrier in the innate immune response. TLRs activate signaling cascades to induce early inflammatory responses to pathogen- and damage-associated molecular patterns. Inflammatory processes are crucial to the emergence and progression of several diseases such as sepsis, cancer or type I diabetes. Thus, manipulating the inflammatory response through small molecule TLR modulators is a promising strategy to treat these conditions. The development of TLR agonists has been pursued to treat infectious diseases, cancer, and allergies and as adjuvants for new vaccines. Excessive or dysregulated TLR signaling has shown to be a main cause of sepsis, autoimmune diabetes and metabolic syndrome, which has triggered increased interest for the design of TLR antagonists for therapeutic purposes. To date, imiquimod, a TLR7 agonist, is the only small molecule TLR agonist that has been approved by the FDA for the topical treatment of dermatological diseases. Several other small molecule TLR modulators are currently being evaluated in clinical trials for various indications. Still, many candidates have been withdrawn from further studies due to severe side effects or lack of efficacy. In particular, TLR4 inhibitors failed in clinical trials as anti-sepsis drugs although inhibition of lipopolysaccharide-induced overactivation of TLR4 was thought to result in protection against sepsis. This may be at least partially explained by recent findings that LPS is recognized intracellularly in a TLR4-independent manner. In addition, the apparently promising approach of TLR4 inhibition in sepsis ignores the fact that there is an innumerable diversity of Gram-negative as well as Gram-positive pro-inflammatory pathogen-associated molecular patterns inducing, often in parallel, sepsis. Thus, for therapeutic efficacy, drugs need to display a broad spectrum of anti-inflammatory activity for multifaceted infections, as well as sufficient bactericidal activity. Here, recent progress on the development and pharmacological characterization of novel TLR modulators will be discussed. In addition, alternative strategies to inhibit TLR-mediated innate immune responses will be presented focusing on synthetic anti-inflammatory peptides that neutralize bacterial pathogenicity factors such as lipopolysaccharides and lipoproteins.
Günther Weindl is Professor of Pharmacology (W2) at the Institute of Pharmacy of Freie Universität Berlin, Germany. He studied Pharmacy at the Ludwig-Maximilians-University in Munich and received his doctoral degree from the Department of Dermatology at the same university. After postdoctoral studies at the University of Tübingen and Freie Universität Berlin, he was appointed Junior Professor of Pharmacology at the Institute of Pharmacy of Freie Universität Berlin in 2011. He was Acting Professor of Pharmacology and Toxicology at the Institute of Pharmacy of the University of Bonn in 2016 and 2017. The research group investigates molecular mechanisms and signaling pathways involved in inflammatory and immunological processes. Current work involves the characterization of new potential anti-inflammatory drugs and autophagy-related processes for inflammatory responses as well as the development of reconstructed tissue models as alternative test systems in pharmacology and toxicology.