A New Platform for Discovering CXCR3 BANTAs for Vitiligo Treatment Many drugs targeting G-protein coupled receptors (GPCRs) are “unbiased antagonists” equally inhibiting G-proteins and receptor internalization. This mode of inhibition can increase receptor concentration on the cell surface, leading to tolerance (reduced drug efficacy after repeated dosing). We found that biased antagonists (BANTAs) of CXCR4 and CCR3 chemokine receptors avoid tolerance by allowing receptor internalization. Discovery of BANTAs for other GPCRs is impeded by the lack of suitable high-throughput screening (HTS) methods. One rotation project in the Gaponenko laboratory is to assist with the development of a two-step HTS approach, measuring Gαi-dependent cAMP and β-arrestin recruitment to the receptor for internalization. This approach will be validated on CXCR4 BANTAs and, in collaboration with Le Poole’s group at Northwestern University, implemented to discover BANTAs of CXCR3 T-cell chemokine receptor, a therapeutic target for vitiligo.In vitiligo, patient skin gradually loses pigmentation as melanocytes are eliminated by skin-infiltrating CD8+ cytotoxic T cells. CXCR3 BANTAs might diminish T cell infiltration and halt depigmentation in vitiligo patients with active disease. CXCR3 is a validated drug target in vitiligo, a difficult to treat autoimmune skin disorder characterized by progressive loss of melanocytes. The disease causes significant discomfort and reduction in the quality of life, but current treatments are only moderately effective. CXCR3 drives infiltration of the skin by CD8+ T lymphocytes that destroy melanocytes and cause depigmentation in patients with vitiligo. Only one antagonist of CXCR3 (AMG487) has been tested in clinical trials but failed to show efficacy. Because AMG487 inhibits both chemotaxis to CXCR3 ligands and receptor internalization, it might have increased CXCR3 on the cell surface and caused tolerance, a potential reason for its failure. We propose to discover BANTAs of CXCR3 that avoid tolerance. BANTAs hold great promise as tolerance-free therapeutics, but have not yet been approved by the US Food and Drug Administration. Approximately 60 million people suffer from vitiligo worldwide. Among them, approximately 40 million exhibit active disease. Lesions are especially apparent in people with ethnic skin. Though several groups, including our own, are devising methods to interfere with vitiligo, no effective treatments exist to halt depigmentation. Treatments, such as transplantation of pigmented skin to lesional areas, or UV exposure can provide temporary relief for some patients, but the treatment is expensive and cumbersome. JAK inhibitors are under consideration but are not without side effects and eventual tolerance. Patients are now lobbying for support to develop effective treatments for their condition. Other patient groups can also benefit, for example patients with alopecia areata, where inhibition of CXCR3 has also been proposed. It will thus be critical to devise methods that have a lasting impact on effector T cell infiltration to the skin and to test their application in mouse models that reflect the human disease.
– Biased Antagonism Of CXCR4 Avoids Antagonist Tolerance.
– Novel Peptide Nanoparticle Biased Antagonist Of CCR3.