Author: Schulz, Ina ; Hirsch, Anna K. H. ; Kraus, Frank ; El Hamdaoui, Yamina ; Plietker, Bernd ; Izzo, Flavia ; Kany, Andreas M. ; Bleisch, Anton ; Friedland, Kristina ; Peslalz, Philipp

Selective modulation of TRPC6 ion channels is a promising therapeutic approach for neurodegenerative diseases and depression. A significant advancement showcases the selective activation of TRPC6 through metalated type-B PPAP, termed PPAP53. This success stems from PPAP53's 1,3-diketone motif facilitating metal coordination. PPAP53 is water-soluble and as potent as hyperforin, the gold standard in this field. In contrast to type-A, type-B PPAPs offer advantages such as gram-scale synthesis, easy derivatization, and long-term stability. Our investigations reveal PPAP53 selectively binding to the C-terminus of TRPC6. Although cryoelectron microscopy has resolved the majority of the TRPC6 structure, the binding site in the C-terminus remained unresolved. To address this issue, we employed state-of-the-art artificial-intelligence-based protein structure prediction algorithms to predict the missing region. Our computational results, validated against experimental data, indicate that PPAP53 binds to the ⁷⁷⁷LLKL⁷⁸⁰-region of the C-terminus, thus providing critical insights into the binding mechanism of PPAP53.

23 Nov 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

Unnatural Endotype B PPAPs as Novel Compounds with Activity against Mycobacterium tuberculosis

Q1 · MEDICINE

Article

Author: Vorbach, Andreas ; Grieshober, Mark ; Momoi, Kyoko ; Braeuning, Albert ; Bleisch, Anton ; Peslalz, Philipp ; Zanger, Ulrich M. ; Izzo, Flavia ; Stenger, Steffen ; Plietker, Bernd ; Kraus, Frank ; Brötz-Oesterhelt, Heike ; Lichtenstein, Dajana ; Hammer, Helen

Pre-SARS-CoV-2, tuberculosis was the leading cause of death by a single pathogen. Repetitive exposure of Mycobacterium tuberculosis(Mtb) supported the development of multidrug- and extensively drug-resistant strains, demanding novel drugs. Hyperforin, a natural type A polyprenylated polycyclic acylphloroglucinol from St. John's wort, exhibits antidepressant and antibacterial effects also against Mtb. Yet, Hyperforin's instability limits the utility in clinical practice. Here, we present photo- and bench-stable type B PPAPs with enhanced antimycobacterial efficacy. PPAP22 emerged as a lead compound, further improved as the sodium salt PPAP53, drastically enhancing solubility. PPAP53 inhibits the growth of virulent extracellular and intracellular Mtb without harming primary human macrophages. Importantly, PPAP53 is active against drug-resistant strains of Mtb. Furthermore, we analyzed the in vitro properties of PPAP53 in terms of CYP induction and the PXR interaction. Taken together, we introduce type PPAPs as a new class of antimycobacterial compounds, with remarkable antibacterial activity and favorable biophysical properties.

International Journal of Molecular Sciences

Antimicrobial Evaluation of Two Polycyclic Polyprenylated Acylphloroglucinol Compounds: PPAP23 and PPAP53

Article

Author: Kraus, Frank ; Plietker, Bernd ; Mohammad, Majd ; Wang, Huanhuan ; Purkayastha, Moushumi ; Bleisch, Anton ; Deshmukh, Meghshree ; Kretschmer, Dorothee ; Matsuo, Miki ; Macek, Boris ; Brötz-Oesterhelt, Heike ; Peslalz, Philipp ; Ammanath, Aparna Viswanathan ; Maier, Lisa ; Vorbach, Andreas ; Götz, Friedrich ; Grießhammer, Anne ; Jin, Tao ; Peschel, Andreas

Polycyclic polyprenylated acylphloroglucinols (PPAPs) comprise a large group of compounds of mostly plant origin. The best-known compound is hyperforin from St. John’s wort with its antidepressant, antitumor and antimicrobial properties. The chemical synthesis of PPAP variants allows the generation of compounds with improved activity and compatibility. Here, we studied the antimicrobial activity of two synthetic PPAP-derivatives, the water-insoluble PPAP23 and the water-soluble sodium salt PPAP53. In vitro, both compounds exhibited good activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium. Both compounds had no adverse effects on Galleria mellonella wax moth larvae. However, they were unable to protect the larvae from infection with S. aureus because components of the larval coelom neutralized the antimicrobial activity; a similar effect was also seen with serum albumin. In silico docking studies with PPAP53 revealed that it binds to the F1 pocket of human serum albumin with a binding energy of −7.5 kcal/mol. In an infection model of septic arthritis, PPAP23 decreased the formation of abscesses and S. aureus load in kidneys; in a mouse skin abscess model, topical treatment with PPAP53 reduced S. aureus counts. Both PPAPs were active against anaerobic Gram-positive gut bacteria such as neurotransmitter-producing Clostridium, Enterococcus or Ruminococcus species. Based on these results, we foresee possible applications in the decolonization of pathogens.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder	Discovery	Germany	Universität Stuttgart	03 Nov 2023
Neurodegenerative Diseases	Discovery	Germany	Universität Stuttgart	03 Nov 2023

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