Member Biography

Background and Rationale: Cyclic peptides occupy an important niche in the realm of pharmaceuticals. Because of their intermediate size (~1–5 kDa), cyclic peptides represent a middle ground between traditional small-molecule drugs and large, protein-based biologics. As such, cyclic peptides combine desirable features of both of these well-established drug classes. Like small molecules, peptides are synthetically accessible and can penetrate deep into tissues and solid tumors. However, because of their larger size, cyclic peptides can bind to therapeutic targets that are inaccessible to small molecules, and with affinity and specificity similar to large biologics. A major focus of my research is to identify and develop new cyclic peptides with therapeutic, diagnostic, and research applications. My primary interest is in developing peptide-based immune checkpoint inhibitors as novel cancer therapeutics. To this end, my lab will employ two well-established and complementary methods of peptide drug discovery, namely phage display and split-intein circular ligation of peptides and proteins (SICLOPPS). Using these techniques, billions of unique cyclic peptides can be screened in a matter of days—far exceeding the pace at which small molecule libraries can be screened using high-throughput techniques. While phage display and SICLOPPS are routinely used in early-stage drug discovery, these techniques suffer from the same fundamental limitation. Specifically, phage display and SICLOPPS libraries are restricted to peptides that contain only the twenty natural amino acids. To overcome this limitation, my lab will apply technology, developed during my graduate and postdoctoral studies, to introduce diverse unnatural amino acids (uAAs) into phage display and SICLOPPS libraries. Introducing uAAs into these libraries will significantly increase their structural and chemical diversity, thereby increasing the likelihood that peptides with desired properties will be identified during screening. We will use this technology to identify cyclic peptide hits for diverse therapeutic targets, including established cancer targets. Our initial focus will be on identifying cyclic peptides that inhibit the CD47–SIRPα interaction and drug-resistant mutants of the BCL-2 family of anti-apoptotic proteins. Cyclic peptides that inhibit the CD47–SIRPα interaction: Widely referred to as the "don’t eat me signal", CD47 is a ubiquitously expressed transmembrane protein that plays key a role in immune regulation. CD47 inhibits phagocytosis of healthy cells by binding to signal regulatory protein α (SIRPα), an inhibitory receptor expressed on the surface of macrophages. The interaction between CD47 and SIRPα signals to the macrophage that the CD47-expressing cell is not a target for phagocytosis. Often, CD47 is used by cancer cells to escape immune regulation. Indeed, overexpression of CD47 is common in a wide range of solid and hematological malignancies, including multiple myeloma, acute myeloid leukemia, non-Hodgkin's lymphoma, and triple-negative breast cancer. CD47 overexpression allows cancer cells to avoid macrophage-mediated phagocytosis and is associated with poor prognosis. Inhibitors of the CD47–SIRPα interaction have been shown to stimulate phagocytosis of cancer cells by macrophages and to have synergistic effects with tumor-targeting antibodies. As such, inhibitors of this interaction are highly promising as next-generation immunotherapeutics. Nearly all clinically validated inhibitors of the CD47–SIRPα interaction are antibodies that are specific to either CD47 or SIRPα. While these antibodies have shown very promising preliminary results, they are costly to manufacture and are associated with adverse side effects, in particular, severe anemia due to opsonization of red blood cells. My goal is to develop bicyclic peptides that can inhibit the CD47–SIRPα interaction. Bicyclic peptides can bind to therapeutic targets with affinity and specificity similar to antibodies; however, because of their smaller size they are synthetically accessible, allowing for fine-tuning of their pharmacological properties. Further, unlike antibodies, bicyclic peptides can penetrate deep into solid tumors. My lab will utilize uAAs to generate libraries of phage-displayed bicyclic peptides. We will then use these libraries to identify bicyclic peptides that bind to CD47 and SIRPα. Once identified, we will evaluate the ability of these peptides to inhibit the CD47-SIRPα interaction in vitro and in cell and animal models of human cancer. Cyclic peptides that inhibit drug-resistant MCL-1 and BCL-2: The intrinsic apoptosis pathway is tightly regulated by the BCL-2 family of proteins, which includes both anti-apoptotic and pro-apoptotic members. Aberrant overexpression of anti-apoptotic proteins within the BCL-2 family causes cells to become resistant to apoptosis and is a common feature of various human cancers. Given their oncogenic properties, inhibitors of anti-apoptotic proteins, in particular MCL-1 and BCL-2, have been extensively investigated as anticancer therapeutics. Indeed, inhibitors that are specific for BCL-2 have been approved for routine treatment of chronic lymphatic leukemia (CLL) and acute myeloid leukemia, and numerous MCL-1-specific inhibitors have shown promising results in clinical trials. However, in recent years, mutations in MCL-1 and BCL-2 have been identified in multiple myeloma and CLL patient-derived samples. These mutations alter protein-drug interactions and causes cancer cells to become refractory to treatment. As such, alternative therapies that are effective against these drug resistant mutants are urgently needed. My goal is to identify cyclic peptides that can inhibit MCL-1 and BCL-2 mutants that are resistant to current therapies. To develop cyclic peptides that inhibit these mutant proteins, my lab will couple SICLOPPS with uAA mutagenesis, to produce large libraries of drug-like cyclic peptides. We will screen these libraries to identify cyclic peptides that bind to and inhibit MCL-1 and BCL-2 variants harboring drug-resistant mutations. These inhibitors will not only provide a starting point for the development of novel therapies but will also be useful tools for exploring the molecular mechanisms of drug resistance.

Psy.D. - Yale University, New Haven, CT 08/2022

Ph.D. - Texas A&M University, College Station, TX 05/2018