These are my notes from discussion section number 6 of Harvard’s Chemistry 101: Chemical Biology Towards Precision Medicine course, taught by Edward Harvey and Chris Gerry on October 13, 2015.
Q. “How is it feasible for generic drug companies to produce drugs using new, simpler syntheses when the pharmaceutical companies who originally discovered the drugs oftentimes cannot afford to make these changes?”
A. (No satisfactory answer given).
Discussion about the bryostatin paper [[Wender 2011]]
- The introduction to the paper is very credulous. It cites an implausible number of biological activities, such as the synaptogenesis and promise for Alzheimer’s, as if they did a Google Scholar search and just plum believed every single thing they found there.
- You could use SILAC or thermal proteome profiling (TPP) to see if bryostatin has any targets other than PKC. If so you would want to propose a lot of followup experiments to narrow down the hits as to which are direct binders and which are indirect. For instance, you might immunodeplete or knock out PKC, a known target, and see if the other hits still bind the compound in its absence. Those that do appear to bind without PKC, you could then try to reconstitute the binding in vitro using recombinant versions of each protein.
- You could try to design more specific analogs of bryostatin that only target one member of the PKC family. One approach would be to get all the PKC amino acid sequences from Uniprot and multiple-align them to look for substitutions near the bryostatin binding site where you might be able to add a group to the bryostatin scaffold to confer specificity.
- You might also be able to confer tissue selectivity on bryostatin. If you specifically wanted to treat a liver disease, you could look for bryostatin analogs that
The original citation for Wender’s 18g-from-14-tons figure for isolation of bryostatin 1 from B. neritina is:
Four lots of pure bryostatin 1, with a total mass of 18 g, were produced… Bugula neritina specimens were collected in shallow waters off the coast of southern California during the spring of 1988 by Marinus, Inc. (Long Beach, CA). This collection consisted of approximately 10,000 gal, corresponding to an estimated damp weight of 28,000 lb of wet animal.