Significance Programmed cell death protein-1 (PD-1) inhibitory antibodies, often referred to as checkpoint inhibitors, have revolutionized the treatment of cancer. However, there is an unmet need for PD-1 agonists to treat autoimmune disorders. Herein, we describe the de novo design of a small, stable PD-1 binding protein and development of a synthetic PD-1 agonist.