Lauryn Kronick, CANFAR Senior Manager of Public Relations, interviews Dr. Linda Chelico and her team at the University of Saskatchewan.
Your research focuses on how HIV works to survive when it enters the body. When someone contracts HIV, how does the body react? What does HIV do to overcome the body’s attacks?
HIV will enter T-cells (or specific immune cells) of the host that it has infected. A number of things happen after that, at many different levels of the immune system, and we study one specific reaction. To narrow it down, we study the immune response that happens at the “protein-protein level.” The HIV virus is made up of proteins, and these proteins must interact with the human proteins in order to overtake the cell, allowing it to then replicate this foreign virus. We study enzymes that specifically try to mutate the HIV’s genetic information to make it non-functional. But HIV is prepared for this, and it produces a protein that then interacts with the human protein, trying to stop it, meaning that it gets degraded. It actually shuts down our response, and that is one of the crucial elements to it surviving in our body, so we are studying that protein-protein interaction.
These human proteins can mutate the genetic information. The genetic information binds to the human proteins and causes our own cells to degrade, so it “tricks” the body into ridding the cells of specific anti-HIV matter. It also completely disrupts much of the cell-to-cell signalling that the immune system needs to respond to the virus.
The host and the viral protein interaction, which is important for the degradation of the host enzymes, causes the HIV to multiply in the body. Can we target this protein-protein interaction with a drug to cause a disruption? If yes, we could get rid of the resistance mechanism for the virus. People have tried using small molecule drugs for disrupting this protein-protein interaction, but the body eventually develops a resistance. We are trying to figure out if we can use protein-based drugs to potentially block the protein-protein interaction, which covers a much larger surface than the small molecule-based drugs.
One part of this project is to make protein-based agents that disrupt the protein-protein interaction, thereby inhibiting the virus’ lifecycle. The other part of this project is to engineer proteins based on the mutations we are attempting to create in the host protein, to make it bind tighter to the viral protein that can act as an inhibitory mechanism, as well as to the viral lifecycle. These are two different aspects we need to look at when developing protein-based drugs, which will eventually lead to the development of better drugs for treating people living with HIV. If this can unlock the kind of natural anti-HIV activity of these human enzymes, then hopefully the future drug will have less side effects compared to the antiretrovirals that are currently used now. Having one drug available is not good enough to treat a virus, because a virus like HIV can develop a resistance.
What progress have you made to date? What are the next steps during the screening process and post-screening process, and do you foresee any challenges do you foresee happening?
We’ve been screening a lot of protein-protein-based inhibitors. These protein-based inhibitors can hit multiple sites on the protein, and to date, what we have done is screened molecules that bind to the viral protein. The binders are currently hitting, not blocking, the protein-protein interaction, but we have metals to make it work, so we are trying to improve the screening process in order to find these binders in the right spot which interacts with the host protein as well. We are currently getting binders to different positions but we have yet to make a binder which inhibits the protein-protein reaction, so we are improving our math and soft-screening to come up with a better binder.
What are some things that excite you with the current screening process, and what are the next steps ahead?
Nobody has done this before. We are the first team to try and make protein-based inhibitors to speculate viral proteins. We are finding out how to make better drugs, but we are also gaining information on the molecular details, concerning how the viral protein interacts with the host protein. We are excited about getting binders to the protein and showing that they are working, in terms of inhibiting the viral life cycle. There is much more to pursue once we achieve that, which will be a part of future studies. Even though we have known about HIV since the 1980s, and then found out more about its biology, researchers thought we knew more about it. But we keep getting surprised by the complexity of HIV and what it can do. We didn’t even know about these specific proteins that could inhibit the virus, because HIV was masking them so well, so we only learned about them approximately 15 years ago. It’s been kind of the “holy grail” where people noticed that there’s a specific molecule that could disrupt virus replication. Many labs have already screened small molecules, which is the traditional approach and they haven’t been successful, so we think because the surface area between the two proteins is so large, that it requires something bigger such as another protein to disrupt it. We are excited to be using a completely different approach than what’s been done in the past, so we have a real chance to make something different, other than the traditional small molecular screen.
How does your research fit with other related projects going on in this field? What are the potential impacts of your research?
There’s a whole field of other people that also study these human proteins that specifically inhibit this virus, so our research differs as we’re not using small molecules; we are using a small protein. The current antiretroviral therapies are good because people are now living longer and they are, for the most part, suppressing the virus. There is less research on the development of new technologies to newer or different interfaces, so that’s a bit different, as we are still trying to develop a different type of drug.
You received a $25,000 Innovation Research Grant from CANFAR. These funds are directed towards pilot projects; do you see larger research projects coming from this unique approach that you are taking?
Yes: we are doing high-risk research and we are confident that it will succeed. We are hopeful that once we get the results, we can pursue a lot of different questions and apply for future grants.
Story by Lauryn Kronick, CANFAR Senior Manager of Public Relations.
Posted on Tuesday, July 25, 2017.