Lasso peptides form a growing family of fascinating ribosomally-synthesized and
post-translationally modified peptides produced by bacteria. They contain 15 to 24 residues and
share a unique interlocked topology that involves an N-terminal 7 to 9-residue macrolactam ring
where the C-terminal tail is threaded and irreversibly trapped. The ring results from the
condensation of the N-terminal amino group with a side-chain carboxylate of a glutamate at
position 8 or 9 or an aspartate at position 7 8 or 9. The trapping of the tail involves bulky
amino acids located in the tail below and above the ring and or disulfide bridges connecting
the ring and the tail. Lasso peptides are subdivided into three subtypes depending on the
absence (class II) or presence of one (class III) or two (class I) disulfide bridges. The lasso
topology results in highly compact structures that give to lasso peptides an extraordinary
stability towards both protease degradation and denaturing conditions. Lasso peptides are
generally receptor antagonists enzyme inhibitors and or antibacterial or antiviral (anti-HIV)
agents. The lasso scaffold and the associated biological activities shown by lasso peptides on
different key targets make them promising molecules with high therapeutic potential. Their
application in drug design has been exemplified by the development of an integrin antagonist
based on a lasso peptide scaffold. The biosynthesis machinery of lasso peptides is therefore of
high biotechnological interest especially since such highly compact and stable structures have
to date revealed inaccessible by peptide synthesis. Lasso peptides are produced from a linear
precursor LasA which undergoes a maturation process involving several steps in particular
cleavage of the leader peptide and cyclization. The post-translational modifications are
ensured by a dedicated enzymatic machinery which is composed of an ATP-dependent cysteine
protease (LasB) and a lactam synthetase (LasC) that form an enzymatic complex called lasso
synthetase. Microcin J25 produced by Escherichia coli AY25 is the archetype of lasso peptides
and the most extensively studied. To date only around forty lasso peptides have been isolated
but genome mining approaches have revealed that they are widely distributed among
Proteobacteria and Actinobacteria particularly in Streptomyces making available a rich
resource of novel lasso peptides and enzyme machineries towards lasso topologies.
