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ePaper created 2017-03-14, 10:25:37 | version 1.49.03
HEALTH CpG ODN potential antagonist TLR9 e m o s o d n e MyD88 IRAK TRAF6 IKK NF-κB NF-κB activation i o n s e x p r e s TNF-α MIF NO IFN-β IL1.6.8, 10, 12 nucleus SEAP phosphatase activity 1 1 2 DRUG DISCOVERY AND DELIVERY: FOCUS ON INFECTION, INFLAMMATION AND INNATE IMMUNITY Ste f fe n Ru p p, A nke Burg e r- Ke nt is ch e r Immunomodulators for therapy Our central objective is to exploit mechanisms of innate immu- nity in combination with targeted drug delivery for therapy of infections as well as autoimmune and inl ammatory diseases. This idea has been fostered by results already achieved in a joint project (ICON project between Fraunhofer IGB and the Hebrew University, IDR) [1, 2]. Based on these results, we aim to design immune-modulatory compounds in order to ad- dress infections and inl ammatory diseases more effectively. Targeting these compounds directly to the site of infection or inl ammation will support the healing process signii cantly. For infections, stimulating the host’s own defense mechanisms should also be effective against pathogens resistant to the current anti-infectives, enhancing “classical” medication efi ciently. As a i rst target we have identii ed dermatological disorders such as atopic dermatitis, psoriasis and lupus, since they show involvement of innate immunity, including toll-like receptors (TLRs). Currently, the pipeline for mild-to-moderate psoriasis includes at least 22 investigational topical therapies in vari- ous stages of development, including IL-17 antagonizing agents, showing that immune-modulating agents have a high potential as medication. Dermatologic disorders often show a complex interplay between defects in skin barrier func- tion, environmental impact and infectious agents as well as changes in immunity. The second focus is to develop novel drugs and targeted nanomedicine to combat fungal infections caused by fungi such as Candida spp. and viral infections caused by Herpesviri- dae. Since innate immunity is an essential part of combating infectious diseases, a combination of drug development, stimulation of innate immunity and targeted formulation of the respective compounds is an ideal approach to combat infections. The i rst compounds with TLR-modulating activi- ties have been introduced in clinical trials as antiviral agents, indicating the feasibility of this approach. Drug design and selection Discovery of novel agonists and antagonists of innate immune receptors (pattern recognition receptors, PRRs) or the mol- ecules downstream in the signaling pathway related to the in- dicated diseases will be performed as previously described [1] using computational methods by our partner, Hebrew Univer- sity. For example, for TLRs that have a published set of small molecule agonists / antagonist, models are based on physical and chemical properties of ligands and will serve as i lters for scoring and picking top candidates from huge (millions) numbers of commercially available molecules. Modeling and docking is performed in iterations, building on experimental screening results [1, 3]. A library of 200 – 300 compounds is dei ned initially and smaller libraries are employed for subse- quent screenings for each newly addressed PRR or group of PRRs [1]. Targeted delivery systems Liposomes (NP) are potent drug delivery systems that protect the drug from degradation, improve its pharmacokinetic prop- erties and deliver a relatively high drug payload. For efi cient 6 0