Researchers have identified new drug candidates that may be able to prevent HIV-infected cells from escaping detection by the immune system.
A team from the Univerisity of Pittsburgh School of Medicine in the US made the discovery.
Current therapy, called antiretroviral therapy, prevents HIV from multiplying which reduces the virus’ amount in the body to an undetectable level but it isn’t a cure.
“We have excellent antiretroviral drugs that suppress HIV, but unfortunately, none of them clear the virus. If someone with HIV stops taking their medication, the infection will rebound,” Thomas Smithgall, a pharmacology professor at the University of Pittsburgh and one of the study’s authors, said in a statement.
“HIV establishes a reservoir of infected cells that lay dormant even in the presence of antiretroviral therapy, hiding from immune system detection. We think we’ve uncovered a key to unmasking that reservoir,” he added.
The team, which published its findings in the journal Cell Chemical Biology, created compounds called PROTACs that can impact the protein Nef (for Negative Regulatory Factor) which plays a key role in HIV infection.
Nef helps HIV-infected cells avoid being detected by manipulating signs on the surface of these cells, making them invisible to the immune system.
Nef proteins are also linked to an increased immunodeficiency and the virus’ replication inside the organism.
“A protein like Nef is often considered undruggable because it doesn’t have a defined binding site for drug action,” Lori Emert-Sedlak, a research associate professor at the University of Pittsburgh and lead author of the study, said in a statement.
“Our existing Nef inhibitors, which only bind to Nef, block some Nef functions extremely well, but don’t touch other functions, many of which are critical for HIV infection”.
'Great deal of excitement'
Researchers looked for a compound that could mark the protein for “degradation,” which would block its functions. It would also allow for HIV antigens “to be restored” at the surface of cells infected with the virus so the immune system can kill them.
Partnering with the biotechnology company Fox Chase Therapeutics Discovery, Inc., the team found two molecules that worked as Nef binders, which formed the drug candidates.
“In general, the PROTAC approach has generated a great deal of excitement at drug companies, but they’ve been almost entirely targeted to proteins involved in cancers,” Smithgall said.
“Our Nef-directed PROTACs are one of the first examples targeting infectious diseases. In theory, this approach should be applicable to proteins from other viruses that serve functions similar to HIV Nef”.
Researchers warned, however, that there are many major steps required before potential clinical trials.
Smithgall’s team plans future research regarding how exactly the Nef degradation is working as well as pursuing preclinical testing in animal models.
“Finding a small molecule that bound selectively to Nef, that was the hardest part,” Smithgall said.
“Now we have to keep going with medicinal chemistry optimisation and see how well it works against the HIV reservoir in an animal model”.
