The long-term objective of the research proposed here is to set the stage for the discovery of a new class of orally bioavailable, small-molecule drugs that target the PD-1 protein for the treatment of patients with Alzheimer?s Disease (AD) or mild cognitive impairment (MCI). Inhibition of PD-1 in mice by anti-PD-1 monoclonal antibodies (mAbs) has been shown to lead to the recruitment of monocyte-derived macrophages in the brain, clearance of cerebral amyloid-b plaques, and improved cognitive performance. Peripheral blood mononuclear cells (PBMCs) from patients with AD or MCI, or age-matched healthy controls support a role of the PD-1/PD-L1 pathway in the neuroinflammation associated with AD. PD-1 inhibitors have had a dramatic impact in oncology as a member of a new class of drugs called immune checkpoint inhibitors. These drugs, however, can have serious side effects including a life-threatening runaway immune response, termed a cytokine storm. When they occur, these side effects are difficult to manage, especially since all current PD-1 inhibitors are monoclonal antibodies (mAbs) that have long half-lives in patients (typically several weeks) making timely drug removal nearly impossible. Small-molecule anti-PD-1 drugs would offer safety advantages due to their shorter half-lives (typically dosed once or twice daily). This is particularly important in elderly patients with AD or MCI. Identifying small-molecules that bind to PD-1 and disrupt the interaction of PD-1 with its ligands (PD-L1 and PD-L2) has proven to be very difficult. The research proposed in this supplement will use one of the key strategies from the parent Avant Garde award for the HIV-1 gp41 target but apply it to PD-1. Specifically, we aim to use scFv fragments against the CC? loop and/or the FG loop to stabilize a conformation of PD-1 that presents an exposed pocket suitable for small-molecule drug discovery. If successful, this work could set the stage for the discovery of anti-PD-1 drugs that could have utility for the treatment of AD. Importantly, the learnings from work with each of these drug targets are likely to help the efforts with the other.
This project aims to set the stage for discovery of a new class of orally bioavailable small- molecule drugs to treat Alzheimer?s Disease. The molecular target for this potential new class of drugs is the PD-1 protein. This new class of drugs would offer safety advantages, as compared to monoclonal antibody treatments that target the PD-1 protein, that are particularly important in the elderly.
