Funded by the German Federal Foreign Office

German Federal Foreign Office
DAAD Global Centres
Charité
Martin Luther Universität Halle-Wittenberg
Leibniz Institute of Plant Biochemistry
National Autonomous University of Mexico
University of Havana
A novel ACE2 decoy for both neutralization of SARS-CoV-2 variants and killing of infected cells

A novel ACE2 decoy for both neutralization of SARS-CoV-2 variants and killing of infected cells

by | Jun 13, 2023 | Publications, Virology

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to millions of infections and deaths worldwide. As this virus evolves rapidly, there is a high need for treatment options that can win the race against new emerging variants of concern. Here, we describe a novel immunotherapeutic drug based on the SARS-CoV-2 entry receptor ACE2 and provide experimental evidence that it cannot only be used for (i) neutralization of SARS-CoV-2 in vitro and in SARS-CoV-2-infected animal models but also for (ii) clearance of virus-infected cells. For the latter purpose, we equipped the ACE2 decoy with an epitope tag. Thereby, we converted it to an adapter molecule, which we successfully applied in the modular platforms UniMAB and UniCAR for retargeting of either unmodified or universal chimeric antigen receptor-modified immune effector cells. Our results pave the way for a clinical application of this novel ACE2 decoy, which will clearly improve COVID-19 treatment.

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Advancing Multicomponent Strategies to Macrobicyclic Peptides

Advancing Multicomponent Strategies to Macrobicyclic Peptides

by | May 12, 2023 | Bioactive Compounds, Publications

Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected β-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.

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Parasite Metalo-Aminopeptidases as Targets in Human Infectious Diseases

Parasite Metalo-Aminopeptidases as Targets in Human Infectious Diseases

by | Apr 5, 2023 | Bioactive Compounds, Publications

Background

Parasitic human infectious diseases are a worldwide health problem due to the increased resistance to conventional drugs. For this reason, the identification of novel molecular targets and the discovery of new chemotherapeutic agents are urgently required. Metalo-aminopeptidases are promising targets in parasitic infections. They participate in crucial processes for parasite growth and pathogenesis.

Objective

In this review, we describe the structural, functional and kinetic properties, and inhibitors, of several parasite metalo-aminopeptidases, for their use as targets in parasitic diseases.

Conclusion

Plasmodium falciparum M1 and M17 aminopeptidases are essential enzymes for parasite development, and M18 aminopeptidase could be involved in hemoglobin digestion and erythrocyte invasion and egression. Trypanosoma cruzi, T. brucei and Leishmania major acidic M17 aminopeptidases can play a nutritional role. T. brucei basic M17 aminopeptidase down-regulation delays the cytokinesis. The inhibition of Leishmania basic M17 aminopeptidase could affect parasite viability. L. donovani methionyl aminopeptidase inhibition prevents apoptosis but not the parasite death. Decrease in Acanthamoeba castellanii M17 aminopeptidase activity produces cell wall structural modifications and encystation inhibition. Inhibition of Babesia bovis growth is probably related to the inhibition of the parasite M17 aminopeptidase, probably involved in host hemoglobin degradation. Schistosoma mansoni M17 aminopeptidases inhibition may affect parasite development, since they could participate in hemoglobin degradation, surface membrane remodeling and eggs hatching. Toxoplasma gondii M17 aminopeptidase inhibition could attenuate parasite virulence, since it is apparently involved in the hydrolysis of cathepsin Cs- or proteasome-produced dipeptides and/or cell attachment/invasion processes. These data are relevant to validate these enzymes as targets.

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Aptamers as Novel Binding Molecules on an Antimicrobial Peptide-Armored Composite Hydrogel Wound Dressing for Specific Removal and Efficient Eradication of Pseudomonas aeruginosa

Aptamers as Novel Binding Molecules on an Antimicrobial Peptide-Armored Composite Hydrogel Wound Dressing for Specific Removal and Efficient Eradication of Pseudomonas aeruginosa

by | Mar 2, 2023 | Bioactive Compounds, Publications

Here we present for the first time a potential wound dressing material implementing aptamers as binding entities to remove pathogenic cells from newly contaminated surfaces of wound matrix-mimicking collagen gels. The model pathogen in this study was the Gram-negative opportunistic bacterium Pseudomonas aeruginosa, which represents a considerable health threat in hospital environments as a cause of severe infections of burn or post-surgery wounds. A two-layered hydrogel composite material was constructed based on an established eight-membered focused anti-P. aeruginosa polyclonal aptamer library, which was chemically crosslinked to the material surface to form a trapping zone for efficient binding of the pathogen. A drug-loaded zone of the composite released the C14R antimicrobial peptide to deliver it directly to the bound pathogenic cells. We demonstrate that this material combining aptamer-mediated affinity and peptide-dependent pathogen eradication can quantitatively remove bacterial cells from the “wound” surface, and we show that the surface-trapped bacteria are completely killed. The drug delivery function of the composite thus represents an extra safeguarding property and thus probably one of the most important additional advances of a next-generation or smart wound dressing ensuring the complete removal and/or eradication of the pathogen of a freshly infected wound.

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