A Journey into the Blue: Current Knowledge and Emerging Insights into Marine-Derived Peptaibols.

Peptaibols represent a large family of membrane-active, linear fungal peptides, with variable lengths from 5 to 21 α-amino acid residues. As products of nonribosomal peptide synthetase (NRPS) biosynthetic machinery, they encompass several non-proteinogenic amino acids, particularly the Cα-tetrasubstituted residues, such as α-aminoisobutyric acid (Aib) and its homologue isovaline (Iva). Further distinctive features include an N-acyl terminus, such as an acetyl group, and a C-terminus containing an amino alcohol residue (such as phenylalaninol, leucinol, and valinol, among others), which neutralize charges at both termini and confer them a hydrophobic nature. Peptaibols not only represent the most abundant class among nonribosomal peptides, but they have also attracted continuous scientific interest due to their diverse pharmacological properties, including antimicrobial, cytotoxic, antifungal, and antiviral activities. In this review, we present for the first time the recently explored chemodiversity of fungal peptaibiotics derived from marine sources, with a particular focus on peptaibols. We discuss their distinctive structural features, chemical characterization, biosynthetic pathways, and biological activity profiles, with the aim of supporting ongoing research toward their development as potential pharmaceutical agents.