Nature's New Peptides: Nitrile-Containing RiPPs Discovered as Potent Protease Inhibitors
Background
Nitrile-containing natural products are widely distributed across all kingdoms of life, and synthetic peptides incorporating nitrile groups are highly valued in medicinal chemistry for their therapeutic potential. Despite this, the presence of a nitrile group in ribosomally synthesized and post-translationally modified peptides (RiPPs) – a diverse class of natural products – was previously unprecedented. This study addresses the fundamental knowledge gap regarding the existence and biosynthetic pathways of nitrile-containing RiPPs in nature.
Results
The study successfully identified a groundbreaking biosynthetic pathway, revealing that the AS-like protein encoded within the BGC directly converts the C-terminal carboxylate of the precursor peptide into a nitrile group, a modification never before observed in RiPPs. Furthermore, they discovered that the MNIO enzyme performs stereoselective β-hydroxylation specifically on aspartate residues, while the αKG-HExxH enzyme catalyzes a similar stereoselective β-hydroxylation on proline residues. These intricate modifications culminate in the formation of the final product. The newly discovered RiPP, named Nitrilobacillin, was functionally characterized as a potent cysteine protease inhibitor, demonstrating that nature can produce 'warhead' structures functionally analogous to those found in synthetic therapeutics, such as the active ingredient in Paxlovid. This finding significantly expands the known structural and functional diversity of RiPPs.
Why It Matters
This discovery profoundly expands our understanding of the chemical diversity and biosynthetic capabilities of RiPPs, revealing a novel post-translational modification pathway for nitrile formation. The identification of Nitrilobacillin as a potent cysteine protease inhibitor highlights a striking parallel between natural product strategies and established synthetic drug design, suggesting new avenues for drug discovery. These novel RiPPs or their derivatives could serve as innovative scaffolds for developing new antimicrobial, antiviral, or anticancer agents, potentially paving the way for preclinical development and future human trials. This work underscores the vast untapped potential within natural product chemistry.