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Design of small molecule inhibitors of type III secretion system ATPase EscN from enteropathogenic Escherichia coli

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Bzdzion L., Krezel H., Wrzeszcz K., Grzegorek I., Nowinska K., Chodaczek G., Swietnicki W.

2017

vol. 64

issue 1

49-63

Enteropathogenic E. coli (EPEC) is a human pathogen using type III secretion system for delivery of proteins directly into the human host. The system contains a single ATPase, EscN, which is essential for uncoupling of proteins from their complexes with chaperones before the delivery. The structure of EscN ATPase (PDB code: 2obm) was used to screen computationally for small molecule inhibitors blocking its active site. Two lead candidates were examined but only one, Compound 54, was selected for further optimization. After extended QSAR optimization, two derivatives were found to be competitive inhibitors of EscN capable of blocking ATPase activity with a Ki below 50 µM. One candidate, WEN05-03, with a Ki=16±2 µM, was also minimally toxic to mammalian cells as determined by other assays. In the cell infection model of HeLa cells with EPEC, Compound WEN05-03 completely blocked actin cluster formation at 100 µM concentration, when analyzed by confocal microscopy. The second best inhibitor of EscN ATPase activity was WEN04-34 with a Ki=46±2 µM. However, the compound was highly toxic to the BALB/3T3 cell line. In summary, the work identifies a compound blocking bacterial ATPase in its active site without causing cellular toxicity to the host cells. It is the first report showing feasibility of using bacterial virulence system ATPase as a target for safe, non-toxic compounds and offering a proof-of-concept for non-antibiotic alternatives.

Nowe celowane leki małocząsteczkowe w leczeniu astmy

63%

Romantowski J., Niedoszytko M. N.

Alergia Astma Immunologia - przegląd kliniczny

2019

vol. 24

issue 3

131-136

Asthma is a common chronic bronchial disease that is a major social problem in the world. Despite significant advances in inhalation therapy in recent decades, severe asthma remains a challenge for modern medicine. The heterogeneity of the mechanisms behind the severity of symptoms and resistance to classic inhalation drugs significantly impedes the search for targeted drugs in a group of patients with no satisfactory disease control based on basic drugs. To date, research on new drugs in severe asthma has mainly focused on antibody synthesis. However, a relatively large molecule of these drugs imposes some restrictions on the way of their administration and diagostic targets. The article discusses new therapeutic options associated with low molecular weight drugs under 900 Dalton being developed in recent years

Astma jest częstą chorobą przewlekła oskrzeli, stanowiącą istotny problem społeczny na świecie. Pomimo znacznego postępu w terapii wziewnej w ostatnich dekadach, astma ciężka stanowi nadal wyzwanie dla współczesnej medycyny. Heterogenność mechanizmów stojących za nasileniem objawów i oporność na klasyczne leki wziewne znacznie utrudnia poszukiwanie celowanych leków w grupie chorych nie uzyskujących zadowalającej kontroli choroby w oparciu o podstawowe leki. Dotychczasowe badania nad nowymi lekami w ciężkiej astmie koncentrują się głównie na syntezie przeciwciał. Jednak relatywnie duża cząsteczka tych leków nakłada na nie pewne ograniczenia związane z drogą podania i możliwymi punktami uchwytu. Niniejszy artykuł omawia nowe możliwości terapeutyczne związane z opracowywanymi w ostatnich latach lekami małocząsteczkowymi o masie poniżej 900 Daltonów.

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1 Acta Biochimica Polonica

1 Alergia Astma Immunologia - przegląd kliniczny

1 2019

1 2017

1 Bzdzion L.

1 Chodaczek G.

1 Grzegorek I.

1 Krezel H.

1 Niedoszytko M. N.

1 Nowinska K.

1 Romantowski J.

1 Swietnicki W.

1 Wrzeszcz K.

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Design of small molecule inhibitors of type III secretion system ATPase EscN from enteropathogenic Escherichia coli

Nowe celowane leki małocząsteczkowe w leczeniu astmy