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Molecules (Basel, Switzerland) Oct 2021Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and...
Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.
Topics: Aedes; Animals; Antiviral Agents; Camptothecin; Drug Discovery; Female; High-Throughput Screening Assays; Humans; Insecticide Resistance; Insecticides; Larva; Mosquito Vectors; Motor Activity; Pandemics; Topoisomerase I Inhibitors; Vector Borne Diseases; Virus Replication; Zika Virus
PubMed: 34684807
DOI: 10.3390/molecules26206226 -
Journal of Biomolecular Structure &... May 2021In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to...
In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to identify commercially available drugs in order to repurpose them against coronavirus by the means of structure-based virtual screening. In addition, ZINC15 library was used to identify novel leads against main proteases. Human TMPRSS2 3D structure was first generated using homology modeling approach. Our molecular docking study showed four potential inhibitors against Mpro enzyme, two available drugs (Talampicillin and Lurasidone) and two novel drug-like compounds (ZINC000000702323 and ZINC000012481889). Moreover, four promising inhibitors were identified against TMPRSS2; Rubitecan and Loprazolam drugs, and compounds ZINC000015988935 and ZINC000103558522. ADMET profile showed that the hits from our study are safe and drug-like compounds. Furthermore, molecular dynamic (MD) simulation and binding free energy calculation using the MM-PBSA method was performed to calculate the interaction energy of the top-ranked drugs.Communicated by Ramaswamy H. Sarma.
Topics: COVID-19; Cysteine Endopeptidases; Drug Repositioning; Humans; Molecular Docking Simulation; Peptide Hydrolases; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2; Viral Nonstructural Proteins
PubMed: 32306862
DOI: 10.1080/07391102.2020.1758791