To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A?
Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
|---|---|
| Enthalten in: |
International journal of molecular sciences - 24(2023), 7 vom: 06. Apr. |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Zheng, Yang [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 14.04.2023 Date Revised 15.04.2023 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.3390/ijms24076817 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM355521512 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM355521512 | ||
| 003 | DE-627 | ||
| 005 | 20231226064527.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3390/ijms24076817 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1185.xml |
| 035 | |a (DE-627)NLM355521512 | ||
| 035 | |a (NLM)37047792 | ||
| 035 | |a (PII)6817 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Zheng, Yang |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a To Target or Not to Target Schistosoma mansoni Cyclic Nucleotide Phosphodiesterase 4A? |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.04.2023 | ||
| 500 | |a Date Revised 15.04.2023 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Schistosomiasis is a neglected tropical disease with high morbidity. Recently, the Schistosoma mansoni phosphodiesterase SmPDE4A was suggested as a putative new drug target. To support SmPDE4A targeted drug discovery, we cloned, isolated, and biochemically characterized the full-length and catalytic domains of SmPDE4A. The enzymatically active catalytic domain was crystallized in the apo-form (PDB code: 6FG5) and in the cAMP- and AMP-bound states (PDB code: 6EZU). The SmPDE4A catalytic domain resembles human PDE4 more than parasite PDEs because it lacks the parasite PDE-specific P-pocket. Purified SmPDE4A proteins (full-length and catalytic domain) were used to profile an in-house library of PDE inhibitors (PDE4NPD toolbox). This screening identified tetrahydrophthalazinones and benzamides as potential hits. The PDE inhibitor NPD-0001 was the most active tetrahydrophthalazinone, whereas the approved human PDE4 inhibitors roflumilast and piclamilast were the most potent benzamides. As a follow-up, 83 benzamide analogs were prepared, but the inhibitory potency of the initial hits was not improved. Finally, NPD-0001 and roflumilast were evaluated in an in vitro anti-S. mansoni assay. Unfortunately, both SmPDE4A inhibitors were not effective in worm killing and only weakly affected the egg-laying at high micromolar concentrations. Consequently, the results with these SmPDE4A inhibitors strongly suggest that SmPDE4A is not a suitable target for anti-schistosomiasis therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Schistosoma mansoni | |
| 650 | 4 | |a drug target | |
| 650 | 4 | |a phosphodiesterase | |
| 650 | 7 | |a Roflumilast |2 NLM | |
| 650 | 7 | |a 0P6C6ZOP5U |2 NLM | |
| 650 | 7 | |a Cyclic Nucleotide Phosphodiesterases, Type 4 |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 650 | 7 | |a Phosphodiesterase 4 Inhibitors |2 NLM | |
| 650 | 7 | |a Nucleotides, Cyclic |2 NLM | |
| 700 | 1 | |a Schroeder, Susanne |e verfasserin |4 aut | |
| 700 | 1 | |a Kanev, Georgi K |e verfasserin |4 aut | |
| 700 | 1 | |a Botros, Sanaa S |e verfasserin |4 aut | |
| 700 | 1 | |a William, Samia |e verfasserin |4 aut | |
| 700 | 1 | |a Sabra, Abdel-Nasser A |e verfasserin |4 aut | |
| 700 | 1 | |a Maes, Louis |e verfasserin |4 aut | |
| 700 | 1 | |a Caljon, Guy |e verfasserin |4 aut | |
| 700 | 1 | |a Gil, Carmen |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez, Ana |e verfasserin |4 aut | |
| 700 | 1 | |a Salado, Irene G |e verfasserin |4 aut | |
| 700 | 1 | |a Augustyns, Koen |e verfasserin |4 aut | |
| 700 | 1 | |a Edink, Ewald |e verfasserin |4 aut | |
| 700 | 1 | |a Sijm, Maarten |e verfasserin |4 aut | |
| 700 | 1 | |a de Heuvel, Erik |e verfasserin |4 aut | |
| 700 | 1 | |a de Esch, Iwan J P |e verfasserin |4 aut | |
| 700 | 1 | |a van der Meer, Tiffany |e verfasserin |4 aut | |
| 700 | 1 | |a Siderius, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Sterk, Geert Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, David |e verfasserin |4 aut | |
| 700 | 1 | |a Leurs, Rob |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t International journal of molecular sciences |d 2008 |g 24(2023), 7 vom: 06. Apr. |w (DE-627)NLM185552161 |x 1422-0067 |7 nnns |
| 773 | 1 | 8 | |g volume:24 |g year:2023 |g number:7 |g day:06 |g month:04 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3390/ijms24076817 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 24 |j 2023 |e 7 |b 06 |c 04 | ||