Details
| Original language | English |
|---|---|
| Article number | e202112295 |
| Journal | Angewandte Chemie - International Edition |
| Volume | 61 |
| Issue number | 5 |
| Publication status | Published - 18 Jan 2022 |
| Externally published | Yes |
Abstract
Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- General Chemistry
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In: Angewandte Chemie - International Edition, Vol. 61, No. 5, e202112295, 18.01.2022.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors
AU - Kaya, Cansu
AU - Walter, Isabell
AU - Yahiaoui, Samir
AU - Sikandar, Asfandyar
AU - Alhayek, Alaa
AU - Konstantinović, Jelena
AU - Kany, Andreas M.
AU - Haupenthal, Jörg
AU - Köhnke, Jesko
AU - Hartmann, Rolf W.
AU - Hirsch, Anna K.H.
N1 - Funding Information: The authors are grateful for the technical support provided by Simone Amann, Jeannine Jung, Selina Wolter and Dennis Jener. A.K.H. Hirsch gratefully acknowledges funding from the Helmholtz‐Association's Initiative and Networking Fund. J. Konstantinović acknowledges funding by the Alexander von Humboldt Foundation. Open Access funding enabled and organized by Projekt DEAL.
PY - 2022/1/18
Y1 - 2022/1/18
N2 - Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.
AB - Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data. Inspired by the natural LasB substrate, the original fragment was successfully merged and grown. The optimized inhibitor is accessible via simple chemistry and retained selectivity with a substantial improvement in activity, which can be rationalized by the crystal structure of LasB in complex with the inhibitor. We also demonstrate an improved in vivo efficacy of the optimized hit in Galleria mellonella larvae, highlighting the significance of this class of compounds as promising drug candidates.
UR - http://www.scopus.com/inward/record.url?scp=85121007109&partnerID=8YFLogxK
U2 - 10.1002/anie.202112295
DO - 10.1002/anie.202112295
M3 - Article
C2 - 34762767
AN - SCOPUS:85121007109
VL - 61
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 5
M1 - e202112295
ER -