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Immune System Diseases

Congenital Disorders

Skin and Musculoskeletal Diseases

Synthetic peptide

Enzyme

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Disease Domain	Count

Immune System Diseases	2
Infectious Diseases	1

Top 5 Drug Type	Count

Synthetic peptide	1
Enzyme	1

Top 5 Target	Count

LEKTI(Serine protease inhibitor Kazal-type 5)	1
CXCR4(C-X-C motif chemokine receptor 4)	1

AbstractEndogenous antimicrobial peptides (AMPs) play a key role in the host defense against pathogens. AMPs attack pathogens preferentially at the site of entry to prevent invasive infection. Mycobacterium tuberculosis (Mtb) enters its host via the airways. AMPs released into the airways are therefore likely candidates to contribute to the clearance of Mtb immediately after infection. Since lysozyme is detectable in airway secretions, we evaluated its antimicrobial activity against Mtb. We demonstrate that lysozyme inhibits the growth of extracellular Mtb, including isoniazid-resistant strains. Lysozyme also inhibited the growth of non-tuberculous mycobacteria. Even though lysozyme entered Mtb-infected human macrophages and co-localized with the pathogen we did not observe antimicrobial activity. This observation was unlikely related to the large size of lysozyme (14.74 kDa) because a smaller lysozyme-derived peptide also co-localized with Mtb without affecting the viability. To evaluate whether the activity of lysozyme against extracellular Mtb could be relevant in vivo, we incubated Mtb with fractions of human serum and screened for antimicrobial activity. After several rounds of sub-fractionation, we identified a highly active fraction-component as lysozyme by mass spectrometry. In summary, our results identify lysozyme as an antimycobacterial protein that is detectable as an active compound in human serum. Our results demonstrate that the activity of AMPs against extracellular bacilli does not predict efficacy against intracellular pathogens despite co-localization within the macrophage. Ongoing experiments are designed to unravel peptide modifications that occur in the intracellular space and interfere with the deleterious activity of lysozyme in the extracellular environment.

01 Jul 2024·Journal of Dermatological Science

LEKTI domain 6 displays anti-inflammatory action in vitro and in a murine atopic dermatitis model

Article

Author: Mägert, Hans-Jürgen ; Filor, Viviane ; Forssmann, Wolf-Georg ; Vidak, Jonathan ; Rüger, Marc ; Canbolat, Pascal ; Wilzopolski, Jenny ; Bäumer, Wolfgang ; Kaessmeyer, Sabine

BACKGROUNDLympho-epithelial Kazal-type-related inhibitor (LEKTI) is a serine protease inhibitor consisting of multiple domains. A loss of function mutation is described in Netherton patients that show severe symptoms of atopic lesions and itch.OBJECTIVESLEKTI domain 6 (LD6) has shown strong serine protease-inhibitory action in in vitro assays and thus it was tested in vitro and in vivo for potential anti-inflammatory action in models of atopic skin disease.METHODSHuman skin equivalents were treated with LD6 and an inflammatory reaction was challenged by kallikrein-related endopeptidase 5 (KLK5). Furthermore, LD6 was tested on dorsal root ganglia cells stimulated with KLK5, SLIGRL and histamine by calcium imaging. The effect of topically administered LD6 (0.4-0.8%) in lipoderm was compared to a topical formulation of betamethasone-diproprionate (0.1%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice sensitized to house dust mite antigen. Endpoints were clinical scoring of the mice as well as determination of scratching behaviour.RESULTSKLK5 induced an upregulation of CXCL-8, CCL20 and IL-6 in skin equivalents. This upregulation was reduced by pre-incubation with LD6. KLK5 as well as histamine induced calcium influx in a population of neurons. LD6 significantly reduced the calcium response to both stimuli. When administered onto lesional skin of NC/Nga mice, both LD6 and betamethasone-dipropionate significantly reduced the inflammatory reaction. The effect on itch behaviour was less pronounced.CONCLUSIONTopical administration of LD6 might be a new therapeutic option for treatment of lesional atopic skin.

02 Oct 2023·Amyloid

Human lysozyme inhibits the fibrillation of serum amyloid a protein from systemic AA amyloidosis

Article

Author: Baur, Julian ; Wiese, Sebastian ; Fändrich, Marcus ; Puşcalău-Gîrţu, Ioana ; Forssmann, Wolf-Georg ; Malešević, Miroslav ; Haupt, Christian ; Moderer, Tim ; Ständker, Ludger ; Schmidt, Christoph Q ; Rodríguez-Alfonso, Armando

BACKGROUNDSystemic AA amyloidosis is a world-wide occurring protein misfolding disease in humans and animals that arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein and their deposition in multiple organs.OBJECTIVETo identify new agents that prevent fibril formation from SAA protein and to determine their mode of action.MATERIALS AND METHODSWe used a cell model for the formation of amyloid deposits from SAA protein to screen a library of peptides and small proteins, which were purified from human hemofiltrate. To clarify the inhibitory mechanism the obtained inhibitors were characterised in cell-free fibril formation assays and other biochemical methods.RESULTSWe identified lysozyme as an inhibitor of SAA fibril formation. Lysozyme antagonised fibril formation both in the cell model as well as in cell-free fibril formation assays. The protein binds SAA with a dissociation constant of 16.5 ± 0.6 µM, while the binding site on SAA is formed by segments of positively charged amino acids.CONCLUSIONOur data imply that lysozyme acts in a chaperone-like fashion and prevents the aggregation of SAA protein through direct, physical interactions.

100 Deals associated with PHARIS Biotec GmbH

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100 Translational Medicine associated with PHARIS Biotec GmbH

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Pipeline

Pipeline Snapshot as of 20 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

ALB-408 ( CXCR4 )	HIV Infections More	Clinical
Lympho-Epithelial Kazal-Type Inhibitor (PHARIS Biotec) ( LEKTI )	Dermatitis, Atopic More	Preclinical
Hemoparatide ( PTH1R )	Psoriasis More	Pending