Non-sedating benzodiazepines cause paralysis and tissue damage in the parasitic blood fluke Schistosoma mansoni
| Autor: | Yeunus Mian, V. V. N. Phani Babu Tiruveedhula, John D. Chan, James M. Cook, Michael D. Olp, Paul McCusker, Lalit K. Golani, Guanguan Li, Brian C. Smith, Ranjit Verma, Farjana Rashid |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Schistosoma Mansoni Flatworms RC955-962 Drug Evaluation Preclinical Pharmacology Database and Informatics Methods Benzodiazepines 0302 clinical medicine Arctic medicine. Tropical medicine Medicine and Health Sciences Skin Anthelmintics biology Pharmaceutics GABAA receptor Eukaryota Drugs 3. Good health Praziquantel Infectious Diseases Sedation Schistosoma Schistosoma mansoni Public aspects of medicine RA1-1270 Sequence Analysis Locomotion Research Article medicine.drug Bioinformatics medicine.drug_class 030231 tropical medicine Research and Analysis Methods 03 medical and health sciences Meclonazepam Drug Therapy Sedatives Sequence Motif Analysis Helminths parasitic diseases Parasitic Diseases medicine Animals Flatworm Benzodiazepine Organisms Public Health Environmental and Occupational Health Biology and Life Sciences Apical membrane biology.organism_classification Invertebrates 030104 developmental biology |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 13, Iss 11, p e0007826 (2019) PLoS Neglected Tropical Diseases |
| ISSN: | 1935-2735 |
| DOI: | 10.1371/journal.pntd.0007826 |
| Popis: | Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs. In most cases, control is reliant upon praziquantel (PZQ) monotherapy. However, PZQ is ineffective against sexually immature parasites, and there have also been several concerning reports on cestode and trematode infections with poor PZQ cure-rates, emphasizing the need for alternative therapies to treat these infections. We have revisited a series of benzodiazepines given the anti-schistosomal activity of meclonazepam (MCLZ). MCLZ was discovered in the 1970’s but was not brought to market due to dose-limiting sedative side effects. However, in the decades since there have been advances in our understanding of the benzodiazepine GABAA receptor sub-types that drive sedation and the development of sub-type selective, non-sedating ligands. Additionally, the sequencing of flatworm genomes reveals that parasitic trematodes and cestodes have lost GABAAR-like ligand gated anion channels, indicating that MCLZ’s anti-parasitic target is distinct from the human receptors that drive sedation. Therefore, we have screened a library of classical and non-sedating 1,4-benzodiazepines against Schistosoma mansoni and identified a series of imidazobenzodiazepines that immobilize worms in vitro. One of these hits, Xhe-II-048 also disrupted the parasite tegument, resulting in extensive vacuole formation beneath the apical membrane. The hit compound series identified has a dramatically lower (~1000×) affinity for the human central benzodiazepine binding site and is a promising starting point for the development of novel anti-schistosomal benzodiazepines with minimal host side-effects. Author summary Over 200 million people are infected with schistosomiasis, yet there are limited therapeutic options available to treat this disease. The benzodiazepine meclonazepam is known to cure both intestinal and urinary schistosomiasis in animal and human studies, but dose-limiting sedation has been a barrier to its development. Little is known about the structure-activity relationship of meclonazepam and other benzodiazepines on schistosomes, or the identity of the parasite receptor for these compounds. However, schistosomes lack obvious homologs to the human GABAARs that cause sedation. This indicates that the parasite target of this drug is distinct from the host receptors that underpin dose-limiting side effects of meclonazepam and raises the possibility that benzodiazepines with poor GABAAR affinity may still retain anti-parasitic effects. Here, we report an in vitro screen of various benzodiazepines against schistosomes, and the identification of hit compounds that are active against worms yet display reduced affinity for the human GABAAR that causes sedation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|