Synthesis and Characterization of Derivatives of the Antifungal Peptoid RMG8-8
Erin J Pratt1, Elena I Mancera-Andrade1, Kevin L Bicker1
1Department of Chemistry, Middle Tennessee State University, 1301 E. Main Street, Murfreesboro, Tennessee37132, United States.
Abstract:
Cryptococcal meningitis, caused by the fungal pathogen Cryptococcus neoformans, is a devastating disease with a mortality rate of over 80%. Due to the increasing prevalence of resistance to antifungals and the high mammalian toxicity of current treatments, the development of new antifungal therapies is vital. In an effort to improve the biological properties of a previously discovered antifungal peptoid, termed RMG8-8, an iterative structure-activity relationship study was conducted. This three-round study sought to optimize the structure of RMG8-8 by focusing on three main structural components: the lipophilic tail, aliphatic side chains, and aromatic side chains. In addition to antifungal testing against C. neoformans, cytotoxicity testing was also performed on all derivatives against human liver cells, and select promising compounds were tested for hemolytic activity against human red blood cells. A number of derivatives containing unique aliphatic or aromatic side chains had antifungal activity similar to RMG8-8 (MIC = 1.56 μg/mL), but all of these compounds were more toxic than RMG8-8. While no derivative was improved across all biological tests, modest improvements were made to the hemolytic activity with compound 9, containing isobutyl side chains in positions 2 and 5, compared to RMG8-8 (HC10 = 130 and 75 μg/mL, respectively). While this study did not yield a dramatically optimized RMG8-8 derivative, this result was not totally unexpected given the remarkable selectivity of this compound from discovery. Nonetheless, this study is an important step in the development of RMG8-8 as a viable antifungal therapeutic.
Insights
Researchers optimized an antifungal peptoid, RMG8-8, to combat Cryptococcus neoformans. While no derivative surpassed RMG8-8 in all tests, compound 9 showed improved hemolytic activity, advancing antifungal drug development.
Area of Science:
- Medicinal Chemistry
- Antimicrobial Drug Discovery
- Mycology
Background:
- Cryptococcal meningitis, caused by Cryptococcus neoformans, has a high mortality rate (>80%).
- Existing antifungal treatments face increasing resistance and high mammalian toxicity.
- Novel therapeutic strategies are crucial for treating invasive fungal infections.
Purpose of the Study:
- To optimize the antifungal peptoid RMG8-8 through iterative structure-activity relationship studies.
- To enhance the biological properties of RMG8-8, focusing on efficacy and reduced toxicity.
- To identify improved derivatives with potential as viable antifungal therapeutics.
Main Methods:
- An iterative three-round structure-activity relationship study was performed on RMG8-8.
- Derivatives were synthesized and tested for antifungal activity against Cryptococcus neoformans.
- Cytotoxicity and hemolytic activity assays were conducted on human liver cells and red blood cells, respectively.
Main Results:
- Several derivatives exhibited potent antifungal activity comparable to RMG8-8 (MIC = 1.56 μg/mL).
- However, all novel derivatives displayed increased toxicity compared to the parent compound.
- Compound 9 demonstrated modest improvement in hemolytic activity (HC50 = 130 μg/mL) versus RMG8-8 (HC50 = 75 μg/mL).
Conclusions:
- No single derivative significantly outperformed RMG8-8 across all tested biological parameters.
- The study highlights the inherent selectivity of the original RMG8-8 compound.
- This research represents a significant step towards developing RMG8-8 into a clinically applicable antifungal agent.
