Abstract

Chitinase inhibitors have chemotherapeutic potential
as fungicides, pesticides, and antiasthmatics. Argifin,
a natural product cyclopentapeptide, competitively
inhibits family 18 chitinases in the nanomolar to micromolar
range and shows extensive substrate mimicry.
In an attempt to map the active fragments of this
large natural product, the cyclopentapeptide was
progressively dissected down to four linear peptides
and dimethylguanylurea, synthesized using a combination
of solution and solid phase peptide synthesis.
The peptide fragments inhibit chitinase B1 from
Aspergillus fumigatus (AfChiB1), the human chitotriosidase,
and chitinase activity in lung homogenates
fromamurinemodel of chronic asthma, withpotencies
rangingfromhighnanomolar tohighmicromolar inhibition.
X-ray crystallographic analysis of the chitinaseinhibitor
complexes revealed that the conformations of the linear peptides were remarkably similar to that of the natural product. Strikingly, the dimethylguanylurea fragment, representing only a quarter of the natural product mass, was found to harbor all significant interactions with the protein and binds with unusually high efficiency. The data provide useful information that could lead to the generation of drug-like, natural product-based chitinase inhibitors.