February 17, 2005
[QUICK SUMMARY: ALSA-funded scientists have identified several promising molecules that keep in a safe form the mutant SOD1 protein implicated in inherited ALS.]
Researchers report in this week’s online edition of the Proceedings of the National Academy of Sciences that several molecules in existing libraries of compounds can inhibit, in the lab, the aggregation of mutant superoxide dismutase (SOD1). SOD1 is the protein whose gene is disrupted in some inherited forms of amyotrophic lateral sclerosis (ALS).
The effective molecules give leads toward designing new therapeutics to treat the disease. Harvard investigator Peter Lansbury, Ph.D., said, “The compounds that we have identified have good activity in a test tube, and we are working hard to increase their potency by making and testing numerous variants.
“At the same time,” added Lansbury, who is at the
Funded in part by The ALS Association (ALSA), the team of Harvard investigators tested libraries of compounds, seeking those that would fit in the critical spaces in the SOD1 protein to stabilize this enzyme. SOD1 normally exists as a paired structure. When the pair separates into single units, those units aggregate (or clump) together.
The aggregates of mutant SOD1 apparently are toxic as they form within the nervous system of patients with ALS. In ALS, motor neurons die, producing progressive weakness of muscles critical for moving, speaking, and eventually, breathing. Somehow the mutated SOD1 is killing the motor neurons.
Many different places within the SOD1 protein are altered by different mutations that researchers have identified in families with inherited ALS. About 5 to 10 percent of all ALS cases run in families.
The common aspect to all of these mutations is the disruption of the structure of SOD1—although it continues to work. So it is not the loss of SOD1’s normal function that is responsible for ALS, but the gain of a toxic property, presumably, of sticking to other SOD1 molecules. Stopping the aggregation is thus the goal for many researchers in the field.
The researchers tested more than 1.5 million molecules, with computer software developed by the company, Schrodinger (http://www.schrodinger.com), and found a hundred suggestive structures. Of these compounds, 15 appear to prevent SOD1 aggregation, as the researchers demonstrated experimentally in test tubes. The library was also pre-screened using Lipinski rules, a set of rules that help select molecules with drug-like properties from large chemical databases. “This is the primary reason why the final 15 molecules that came out as candidates have drug like features and properties,” noted study investigator Soumya Ray, Ph.D.
These compounds represent a good starting point for the design of new therapeutics, the investigators wrote in their report. They add that they “hope to obtain a compound that can be administered to SOD-1 transgenic mouse models” of inherited ALS, once these drug leads are further optimized into potential therapeutics.
