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Chloe Leach

Publication Date

2023-05-15

First Advisor

Steven A. Williams

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Biochemistry

Keywords

biology, biochemistry, drug development, lymphatic filariasis, neglected tropical diseases, nematodes

Abstract

Lymphatic filariasis (LF) is a neglected tropical disease, or NTD, that currently burdens over 50 million people worldwide and is caused by three species of nematodes. Currently, mass drug administration (MDA) is the primary method for distributing treatments to endemic countries. However, the drugs distributed on this mass scale don’t target adult nematodes, which occupy the lymphatic system in mammals and cause most of the symptomatic effects of LF. Adult nematodes also produce microfilariae that can be transmitted from host to mosquito vector.. Because of this, there is a need for a new compound that can target both the larval stages of the nematodes as well as the adults. We are investigating how effective semisynthetic derivatives of sesquiterpene lactones from the Neurolaena lobata plant are in terms of killing adult worms and microfilariae. The most effective derivative was found to be neurolenin D mesylate (NDM), in comparison with the natural product neurolenin B (NB). In order to take all of the necessary steps involved with developing a potential drug candidate in order to receive a patent (which is required for a drug to be considered for MDA), we then assessed the mutagenicity and cytotoxicity of NDM in comparison to NB. The Ames test is the gold standard biological assay used to determine the mutagenicity of a given compound. Using this assay, we determined that neurolenin has no mutagenic effects. To assess potential cytotoxic effects of neurolenin derivatives, we used the Cell Counting Kit-8 (CCK-8) test. This assay utilizes cultured HEK 293 cells and a water-soluble tetrazolium salt in order to demonstrate electron transfer in living cells. We determined that neurolenin has no cellular toxicity. Because of the demonstrated activity of neurolenin derivatives against Brugia pahangi and their low levels of mutagenicity and toxicity, we have identified a novel potential drug candidate for the treatment 7 of lymphatic filariasis and potentially other neglected tropical diseases caused by filarial parasites.

Rights

©2023 Chloe Leach. Access limited to the Smith College community and other researchers while on campus. Smith College community members also may access from off-campus using a Smith College log-in. Other off-campus researchers may request a copy through Interlibrary Loan for personal use.

Language

English

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