The sialidases/neuraminidases represent a family of enzymes whose function is important in the
pathogenicity of bacteria and the virulence of influenza. Relenza and Tamiflu represent two drugs
that were developed using structure-based drug design (SBDD) and computational-assisted drug
design (CADD). These drugs target the active site of the influenza neuraminidase A and B (GH-34
family). Sialidases in the GH-33 family could represent novel drug targets for the treatment of
bacterial or parasitic infection. SBDD was employed to develop chemical tools of two GH-33
sialidases, NanB and TcTS.
NanB is a potential drug target for S. pneumoniae. The chemical tool developed for NanB follows
on from work within the Taylor and Westwood research groups, in which a molecule of CHES and a
glycerol were found serendipitously bound within a water channel at an allosteric site. Using this
information as a basis for SBDD an allosteric inhibitor of NanB, Optactin was developed. Within this
work, synthesis of this inhibitor was achieved and optimised. Optactin was then modified to improve
potency. This proceeded through an amide analogue and addition of an arene resulting in a mid-
micromolar inhibitor (IC₅₀: 55.4±2.5 µM). Addition of polar substituents improved potency further
resulting in a low micromolar inhibitor of NanB, Optactamide (IC₅₀: 3.0±1.7 µM). Application of this
tool in vitro demonstrated that NanB and NanA have a role in invasion of S. pneumoniae into lung
epithelial cells.
TcTS is a potential drug target for the treatment of Chagas disease. A CADD approach using a
fragment library was unsuccessful at identifying an allosteric inhibitor of TcTS despite structural
similarity with NanB. A re-task of the CADD approach towards the active site was successful in
identifying an inhibitor of TcTS and a fragment useful for further development. This work sets the
groundwork for the development of a chemical tool targeting TcTS
