Introduction: A Review of Lasso Peptide Research - Lasso Peptides: Bacterial Strategies to Make and Maintain Bioactive Entangled Scaffolds - page 3

the 35 currently known lasso peptides being identified by this way. They are mainly
from proteobacteria and less frequently from actinobacteria. Increasing knowledge
of different types of lasso peptides, their structures, stability, biological properties
and structure-activity relationships and their biosynthetic mechanisms is essential
for developing them as drug design frameworks and deciphering their native func-
tions in nature.
First interests in the field of lasso peptides concerned the understanding of how
the lasso fold is acquired by bacteria (Duquesne et al. 2007b ; Knappe et al. 2009 ;
Yan et al. 2012 ) and the mechanisms of action of these peptides (Maksimov et al.
2012a ; Rebuffat 2012 ). Progressively, the objectives turned towards the discovery
of novel lasso peptides endowed with new bioactivities (Maksimov et al. 2012b ;
Hegemann et al. 2013a , b , 2014 ; Zimmermann et al. 2013 ). Currently, the two main
directions of lasso peptides research focus, on one hand, on the biosynthetic path-
ways and post-translational modification enzymes, and on the other hand on the
discovery of novel lasso peptides to extend the family and on the structure-activ-
ity relationships that connect the lasso topology and its stability to the biological
activities. Advances made in these two directions open the way to bioengineering
of novel bioactive peptides using the lasso topology as a powerful framework. A
proof of concept of the ability of the lasso topology to be prone to epitope grafting
and to the conception of novel bioactive molecules was afforded, using MccJ25 as
the lasso model and the integrin-binding motif RGD as a peptide epitope (Knappe
et al. 2011 ). Moreover, the MccJ25 lasso fold was shown to be prone to amino acid
substitutions at an important number of positions (Pavlova et al. 2008 ; Pan and
Link 2011 ; Ducasse et al. 2012b ), showing the potential of exploiting a diverse
sequence space in the lasso topology. MccJ25 has been demonstrated to be resistant
against degradation in complex fluid biomatrices (serum, plasma, blood) in vitro
and to maintain its antibacterial activity in vivo in a mouse model of Salmonella
infection, while showing no haemolytic activity, suggesting promising therapeutic
utility of the molecule (Lopez et al. 2007 ). Describing novel enzymes endowed with
particular specificities or functions, such as novel proteases or lasso synthetases, is
a subsequent direction that also contributes making the lasso peptide field fasci-
nating. Indeed, other potent naturally occurring drug design scaffolds are already
exploited actively in such directions, in particular the cyclic cystine knot frame-
work found in cyclotides (head-to-tail cyclized macrocyclic peptides from plants;
Craik et al. 2012 ; Poth et al. 2013 ). Similar to lasso peptides, they combine stability,
compactness and tolerance to amino acid substitutions and offer rich possibilities
for the design of bioactive molecules. The different aspects listed here promise to
make the lasso peptide field an expanding direction of research in the course of the
development of synthetic biology; this notion is especially reinforced as cell-free
expression systems have been proved to be amenable to produce modified and cy-
clic peptides (Kawakami et al. 2009 ).
In addition to these directions that are actively pursued at present, other central
questions emerge around the lasso peptide research and open new perspectives.
Those concern both biological/ecological and biochemical/chemical aspects, such
as: What ecological role could be played by lasso peptides in the environments