Mectins as Multifunctional Agents in Drug Discovery

Mectins, a class of macrocyclic lactone compounds, have been pivotal in treating various parasitic infections since their discovery in the late 20th century [1-3]. Due to their broad-spectrum activity and safety profile, the significance of mectins extends beyond their antiparasitic activity, showcasing potential in antiviral and antimicrobial therapies.

Naturally occurring mectins are derived from fermentation products of the soil bacterium Streptomyces avermitilis. They are characterized by a complex structure that includes multiple fused rings and various substituents that contribute to their biological activity (Fig. 1). For instance, ivermectin, one of the most well-known mectins [4, 5], consists of a 16-membered macrocyclic ring with multiple stereocenters. Mectins exert their effects primarily by binding to glutamate-gated chloride channels in nerve and muscle cells of invertebrates. This leads to increased permeability to chloride ions and subsequent paralysis and death of the parasite. This mechanism is supported by detailed studies on their interaction with ion channels [6, 7]. The ADME profile of mectins is characterized by good absorption, extensive distribution, and a prolonged half-life, which makes them effective with infrequent dosing. The pharmacokinetic properties ensure sustained therapeutic levels in the bloodstream, enhancing their efficacy against parasitic infections [1].

Fig. 1. Examples of mectin derivative drugs: avermectin and ivermectin.

Ivermectin, the first mectin discovered, has been extensively used to treat various parasitic infections, including onchocerciasis (river blindness), lymphatic filariasis, and strongyloidiasis. Its discovery and subsequent applications have led to significant reductions in the burden of parasitic diseases worldwide [8]. The selective toxicity of ivermectin and related compounds is due to the absence of glutamate-gated chloride channels in vertebrates, ensuring safety and effectiveness for animal and human use [4, 7, 9-10].

Recent studies have shown that mectins can exhibit antiviral activity by inhibiting the nuclear import of viral proteins, thereby preventing the replication of viruses within host cells (Fig. 2). This mechanism is particularly effective against RNA viruses [8, 11], including HIV, dengue, and SARS-CoV-2. Ongoing research is exploring the use of mectins as broad-spectrum antiviral agents, focusing on optimizing the antiviral properties through chemical modifications and combination therapies and assessing their efficacy and safety in treating viral infections.

Fig. 2. Potential modes of antiviral actions of ivermectin (adopted from [8]).

Interestingly, mectins have shown efficacy against certain bacterial and fungal infections. For example, they have been used to treat dermatophytosis and certain gram-positive bacterial infections [12]. Mectins exhibit antimicrobial properties by disrupting the cell membranes of bacteria and fungi, leading to cell lysis and death. They also inhibit the synthesis of crucial microbial proteins. This unique dual mechanism of action enhances its effectiveness against a broad spectrum of microorganisms and provides an opportunity to develop novel antimicrobial therapies, especially against multi-drug-resistant pathogens.

Emerging research suggests that the unique properties of mectins make them attractive candidates for repurposing and novel therapeutic development [4, 10]. Mectins could be effective in treating a variety of conditions beyond their current uses, including cancer, autoimmune diseases, and neurological disorders. Moreover, advances in biotechnology, such as CRISPR and high-throughput screening, as well as novel drug delivery systems and chemical synthesis techniques, are expected to enhance the discovery, optimization, and therapeutic potential of mectin derivatives.

The development of mectin-based screening libraries and the exploration of new therapeutic applications hold great promise for the future. The libraries, comprising the collections of chemically diverse mectin derivatives, facilitate high-throughput screening and structure-activity relationship studies, accelerating the identification of novel compounds with enhanced activity and reduced toxicity. Mectin-based screening libraries are instrumental in identifying potential treatments for various diseases, such as cancer and neurodegenerative diseases [13, 14].

The creation of mectin-based screening libraries involves the synthesis of numerous mectin analogs with modifications to the macrocyclic ring, side chains, and functional groups, followed by high-throughput screening to assess their biological activity. Life Chemicals Mectin-based Screening Library (Fig. 3) is an example of such a resource, providing a wide array of compounds for drug discovery.

Fig. 3. Representative compounds from the Life Chemicals Mectin-based Screening Library.

In order to diversify and expand your research toolbox, we also offer a number of related screening libraries:

• Veterinary Focused Screening Library (500 compounds)
• AgroChemical Screening Libraries(18,000 compounds): Insecticide, Herbicide, Microbiocide, and Fungicide Screening Sets

Order your custom compound selections and enjoy the most convenient terms and competitive pricing.

Please, contact us at marketing@lifechemicals.com for any additional information and price quotations.

Download SD files with compound structures directly from our Downloads section

References

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11. Varghese, F. S., Kaukinen, P., Gläsker, S., Bespalov, M., Hanski, L., Wennerberg, K., Kümmerer, B. M., Ahola, T. (2016). Discovery of berberine, abamectin, and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Res., 126: 117-124. DOI: 10.1016/j.antiviral.2015.12.012
12. Zhao, J.-H., Xu, X.-J., Ji, M.-H., Cheng, J.-L., Zhu, G.-N. (2011). Design, Synthesis, and Biological Activities of Milbemycin Analogues. J. Agric. Food Chem., 59: 4836-4841. DOI: 10.1021/jf2001926
13. Zhang, J., Nan, X., Yu, H.-T., Cheng, P.-L., Zhang, Y., Liu, Y.-Q., Zhang, S.-Y., Hu, G.-F., Liu, H., Chen, A.-L. (2016). Synthesis, biological activities, and structure−activity relationships for new avermectin analogs. Eur. J. Med. Chem., 121: 422-432. DOI: 10.1016/j.ejmech.2016.05.056
14. Vashchenko, I., Veselovska, M., Dolgonos, G. A., Lukin, O., Poyarkov, A., Kiyenko, T., Gleave, M. E., Fetyukhin, V., Shivanyuk, A., Gentile, F., Cherkasov, A. (2023). On regioselective monoacylation of abamectin and ivermectin aglycones. Tetrahedron, 149: 133713. DOI: 10.1016/j.tet.2023.133713