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SAN FRANCISCO, March 22 (Xinhua) -- Researchers have found a small molecule that was able to block the production of a specific protein involved in low-density lipoprotein (LDL) turnover by stalling only the ribosome that produces that protein.
Reported in the journal PLOS Biology, the discovery of the chemical compound, which halted the production of a small set of proteins while leaving general protein production untouched, suggests a new drug search strategy: find compounds that target undesired proteins before they are even made.
Many of today's therapies for cancer or heart disease are monoclonal antibodies that bind and disable proteins outside the cell. The immunotherapeutic checkpoint inhibitors block suppressor proteins, unleashing the immune system to attack cancer. But they aren't effective against all proteins, can't enter cells and must be delivered via injection.
Ribosomes are large, general-purpose molecular machines that translate genetic instructions in the form of messenger RNA into the proteins used to build cells, the enzymes in charge of cellular housekeeping, and the hormones that carry messages in and between cells. While antibiotics are known to stall the ribosome, they halt production of most proteins, explained Jamie Cate, a University of California, Berkeley, professor of molecular and cell biology and of chemistry.
In the study by Cate and his colleagues at UC Berkeley and Pfizer Worldwide Research and Development, the small molecule, when delivered orally to rats, lowered LDL cholesterol levels, much the way statins do, though by a different mechanism: by lowering the production of the protein PCSK9, short for proprotein convertase subtilisin kexin 9. The chemical stalls the ribosome only when it's producing PCSK9 and a couple of dozen other proteins out of the tens of thousands of proteins the body produces, as shown by a relatively new technique called ribosomal profiling.
Knocking out PCSK9 is known to lower blood levels of LDL cholesterol, the so-called bad cholesterol, presumably lowering risk of cardiovascular disease.
"PCSK9 was just where we started. Now we can think about how to come up with other small molecules that hit proteins that nobody has been able to target before because, maybe, they have a floppy part, or they don' t have a nook or cranny where you can bind a small molecule to inhibit them," Cate was quoted as saying in a news release from UC Berkeley. "This research is saying, we may be able to just prevent the synthesis of the protein in the first place."
Suspecting that the small molecule, a multi-ringed chlorinated compound, could serve as a template, like a key blank that can be machined to open a specific lock, Cate said "we now have this key blank that we can cut in a number of different ways to try to go after undruggable proteins in a number of different disease states."
The molecule was discovered by Pfizer labs through live-cell screening for compounds that lower production of the protein PCSK9, which regulates the recycling of the LDL receptor.
