Trypanosomatids rely on peptidases as potent virulence factors and were recently found to contain a unique set
of natural peptidase inhibitors not found in higher eukaryotes or in yeast, but present in a limited number of bacteria. Chagasin,
identified in Trypanosoma cruzi, is a tight-binding, high affinity inhibitor of papain-like cysteine peptidases that has
an Ig-like fold and inactivates target enzymes through a limited number of contacts mediated by a few conserved residues
on three exposed loops. Chagasin homologues in other protozoa and bacteria are mostly single genes named ICPs, and together
with chagasin compose family I42 at MEROPS, the peptidase and peptidase inhibitors database
[http://merops.sanger.ac.uk/]. The biological function of chagasin/ICPs seems to vary depending on the organism, but
generally, the current studies point to a role in controlling the activity of endogenous parasite CPs, influencing parasite
differentiation, virulence and different aspects of the host response to infection. More recently, natural inhibitors of serine
peptidases that share similarity to bacterial ecotins were identified in trypanosomatids and named ISPs. Ecotins are specific
to trypsin-fold serine peptidases, enzymes which are not present in trypanosomatids. ISPs are limited to Trypanosomes
and Leishmania and to date, only ISP2 proven to have an inhibitory function. In Leishmania, ISP2 seems to control
the activity of host SPs at the initial stages of infection in order to ensure subsequent parasite survival in macrophages.
The main aspects of chagasin/ICP biochemistry, structure and biological function and the recent findings on ISPs will be
covered in this review.