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Macrophage-Targeting Oligopeptides from Mortierella alpina

Summary

This research explores how certain fungi can produce molecules that could improve drug delivery to specific cells in the body. Scientists discovered that a fungal enzyme can create various versions of a molecule called malpinin, which can carry other substances into immune cells called macrophages. This discovery could lead to better ways to deliver medicines to specific cells in the body. Impacts on everyday life: – Could lead to more effective targeted drug treatments with fewer side effects – May improve treatment of diseases affecting immune cells – Demonstrates sustainable ways to produce pharmaceutical compounds using fungi – Could reduce costs of drug manufacturing through biological production methods – May enable development of new medical imaging techniques

Background

The realm of natural products from early diverging fungi like Mortierella species is largely unexplored. These fungi have traditionally been used for polyunsaturated fatty acid production in the food industry but have not been considered as non-ribosomal peptide (NRP) producers. Recent investigations revealed their potential for producing small oligopeptides of pharmaceutical interest.

Objective

To identify and characterize the nonribosomal peptide synthetase (NRPS) MalA that catalyzes the biosynthesis of surface-active biosurfactants called malpinins. Additionally, to investigate the substrate specificity of adenylation domains and explore the potential for producing novel malpinin variants through precursor-directed biosynthesis.

Results

The study identified the malpinin synthase MalA and revealed high substrate flexibility in certain modules. This led to the production of 20 new malpinin variants from a single enzyme. The researchers successfully incorporated artificial, click-functionalized amino acids which allowed post-biosynthetic coupling to fluorophores. The fluorescent malpinin conjugates were shown to penetrate mammalian cell membranes through phagocytosis-mediated mechanisms.

Conclusion

The research demonstrates that substrate profiling of adenylation domains is a powerful tool for identifying flexible NRPS modules and highlights basal fungi as a source of chemically tractable compounds for pharmaceutical applications. The study also reveals malpinins as potential carrier peptides for targeted drug delivery to macrophages.
  • Published in:Chemical Science,
  • Study Type:Laboratory Research,
  • Source: 10.1039/d2sc00860b
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