Actions of Camptothecin Derivatives on Larvae and Adults of the Arboviral Vector Aedes aegypti.

Frederick A Partridge,Milly A I Lake,David B Sattelle,Rebecca A Lees,Harry-Jack Mann,Beth C Poulton,Gareth J Lycett

doi:10.3390/molecules26206226

Frederick A Partridge, Milly A I Lake + Show 5 more

Open Access

https://doi.org/10.3390/molecules26206226

Copy DOI

Abstract

Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and Onchocerca volvulus 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 Aedes aegypti 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 A. aegypti larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC50 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 A. aegypti 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.

Highlights

To help to address this problem, the Medicines for Malaria Venture recently launched the Pandemic Response Box, an open-source drug discovery program, where laboratories around the world collaborate by screening a library of structurally diverse compounds selected for potential activity against infective and neglected diseases
Deltamethrin at 10 μ M effectively paralyses the larvae, but some compounds in the library showed some reduction in larval motility
We screened the Medicines for Malaria Venture (MMV) Pandemic Response box in a mosquito larval motility assay, and identified that camptothecin, as well as the derivatives rubitecan and topotecan, had antilarval activity against A. aegypti. This observation is concordant with previous observations of camptothecin-related compounds having insecticidal properties, no compound from this chemotype reached the market for this use [24]

Summary

Introduction

Humans have had to contend repeatedly with disease epidemics throughout history. Viruses such as Ebola, HIV, SARS-CoV-2, and Zika underscore the vulnerability of the human population to emerging pathogens. Changes in our environment and society such as urbanization, increased travel, and climate change make epidemics more frequent and harder to control [1]. New and emerging infectious diseases, together with problems of antimicrobial resistance, are a challenge to our limited anti-infective medications and other tools for controlling diseases. To help to address this problem, the Medicines for Malaria Venture recently launched the Pandemic Response Box, an open-source drug discovery program, where laboratories around the world collaborate by screening a library of structurally diverse compounds selected for potential activity against infective and neglected diseases

Methods

Results

Conclusion