American scientists have developed the first ever high-throughput, genome-scale, imaging-based platform to investigate protein stability, providing novel therapeutic possibilities for treating HIV, Alzheimer's disease and cancer.
The study, published Tuesday in the journal Cell Reports, involved a platform named Global Arrayed Protein Stability Analysis (GAPSA). GAPSA has been used to find host proteins targeted by the HIV-1 accessory protein Vpu, which allows the virus to replicate.
Sumit Chanda, professor at Stanford Burnham Prebys Medical Discovery Institute, and senior author of the study said: "We selected Vpu as a test case because although some Vpu targets were known, we suspected there were more. Indeed, GAPSA was able to pinpoint several host proteins with anti-viral activity that had not been reported in connection with HIV."
Vpu, HIV's weapon against the innate immune response, triggers the degradation of host proteins meant to protect against HIV infection, thereby helping the virus overcome barriers to infection and replication.
"In this study we screened a set of 433 interferon-stimulated genes (ISGs), genes that become activated in response to infection, against Vpu to create a more comprehensive list of HIV's cellular targets," said Lars Pache, staff scientist in Chanda's lab and co-author of the paper.
Pache said that identifying Vpu target proteins creates an opportunity to find new drugs that block the interaction, potentially preserving host anti-viral proteins and thus limiting HIV infection.
"Importantly, the system can be equally applied to other infectious diseases that evade the immune system, such as Ebola, influenza, Zika and others," Pache added.
Chanda said the technology can also be applied to identify protein degraders that specifically target disease-causing proteins.
"For example, in cancer, we can ask which proteins specifically degrade or destabilize oncoproteins," said Chanda.
"Similarly, with Alzheimer's disease, we can screen for proteins that degrade beta-amyloid and create therapeutic strategies to discretely control the process without disrupting the entire cellular degradation machinery," said Chanda.
