Peptides as Informants in the Design of Novel Vaccines and Drugs

Richard Scott of Peptide Therapeutics, Cambridge, UK has used Acelrys' Catalyst software in work to develop a Meningitis B vaccine.

Diagram illustrates the process of pharmacophoric analysis (click on image to see the diagram at full resolution)

 

Meningitis B is an ideal candidate for routine childhood immunisation, because of the success of conjugate polysaccharide vaccines against Heamophilus influenzae (HIB) - the other major cause of bacterial meningitis. However, the Group-B meningoccus is a very difficult target to hit. The capsular polysaccharide coat is poorly antigenic, so attempts to develop working vaccines against the conjugated, unconjugated or chemically modified forms of this polysaccharide have proved unsuccessful. We have used phage and combinatorial peptide libraries to generate a peptide template for the key antigenic features of the meningococcal polysaccharide. Using Accelrys' Catalyst software, this template was processed to derive a pharmacophore or immunophore which describes these key features in 3-dimensional space.

The immunophore was used to trawl for compounds that possessed some (or all) of the antigenic features of the polysaccharide. By searching small molecule databases, such as the ACD, we identified numerous compounds which were predicted to be antigenically active. Moreover, we have demonstrated experimentally that some of these compounds were indeed active. To date, the best IC50 values are of the order of 10 micromolar, which compares favourably with the rather low affinity of anti-polysaccharide antibodies in general (around 75micromolar). These compounds have provided useful information for the development of vaccines and patent protection.