Development of new drugs is a multi-step process that requires discovery research to identify new compounds that can kill the pathogens; pre-clinical research to optimize the uptake, stability and safety of these compounds; and clinical testing to validate their efficacy in humans. Progression through this pipeline takes a long time (at least 5-10 years) and lots of money (millions of dollars); and most compounds fail at one stage or another. Therefore, they are never developed into useful drugs. At CIDR, we largely focus on the earliest steps of the drug development pipeline. We apply cutting-edge technology, using a systems biology approach to better understand unique aspects of pathogen biology, which allows us to pinpoint critical “targets” for chemotherapeutic intervention. We often partner with scientists outside CIDR (in both Academia and Pharma) to screen libraries of small molecules for activity against these targets, as well as against the infectious disease organisms themselves.
It is possible to combine the strengths of phenotypic and target-based drug discovery by following up the initial “hits” using structure-guided drug development. For whole-cell active small molecules with known targets and tractable chemistry, a “Hit-to-Lead” campaign can be mounted by using medicinal chemistry to synthesize multiple derivatives of the initial hits and selecting for those that show the best combination of target inhibition, whole-cell activity, and pharmacokinetic properties. The CIDR-based Seattle Structural Genomics Center for Infectious Disease (SSGCID) has partnered with several other structural genomics centers to form the Structure-guided Drug Discovery Coalition (SDDC), which is funded by the Bill & Melinda Gates Foundation, to deliver early leads for malaria, TB, and neglected disease drug candidates to our pre-clinical development partners. For the malaria program, two projects are in Hit-to-Lead development and are being tested for activity and specificity versus a human version of the enzyme. Hits were identified from both fragment screening and phenotypic active libraries and co-crystal structures were determined to guide chemistry efforts and lead optimization. The tuberculosis program has identified lead series in two projects, which have good pharmacokinetic attributes and are now being tested in in vivo infection models. The neglected diseases program was initiated in November 2014 and target selection is underway.