Protease Dimer

The new drug target, which is known as a protease dimer, could serve as a model for developing new therapeutics for diseases ranging from cancer to Alzheimer’s.

Researchers at the University of California at San Francisco (UCSF) have now found a new way of targeting the herpes virus that causes Kaposi’s sarcoma, which will return researchers to the idea that protease inhibitors may be useful against the entire herpes virus family, after 2 decades during which this goal seemed out of bounds. Known as a protease dimer, the new drug target might serve as the model for developing therapies for diseases running the entire medical spectrum from cancer to Alzheimer’s say the researchers. The study was published on the Nature Chemical Biology website.

Most of the antiviral drugs in current use work by targeting the areas where viral proteins are active. These drugs use a system whereby enzymes and receptors work together to activate or render harmless a specific protein. This is called “lock and key action,” and causes the receptors to become inactive.

However, the viral enzymes known as proteases, such as exist within the herpes virus family and in HIV, take a specific form known as a “dimer,” and resemble two halves of a whole, looking somewhat like an opened clamshell, when they are stable. Dimers play a crucial role in causing viruses to be infectious but must have both halves of the clamshell in order to enable binding and activation. Back in the 1980’s, scientists blocked the active part of the dimer surface, making it possible to target the HIV protease for drug development, though the herpes virus protease dimer still eludes all efforts to stop it where it starts—at the site of activity, say the researchers.

The UCSF team had a different idea: they thought to prevent the two sides of the dimer from making a connection at the “clamshell” joint so as to prevent activation. A professor of UCSF’s School of Pharmacy explained, “If you disrupt the protein-protein interactions, you don’t need the key to a specific lock. Instead, we’re essentially preventing the lock from being made in the first place.”

Since all the herpes viruses have proteases which are similar in structure, the proteases dimmer is found to work against the entire herpes viral family.