Targeting Nuclear Receptors
Nuclear receptors can bind ligand, leading to a conformational change, homo- or hetero-dimerization, nuclear translocation and DNA binding.
Novel, high-affinity peptides can disrupt this process at multiple pressure points, such as (1) the ligand-binding pocket, (2) the dimerization domain, (3) DNA binding domain, or (4) coactivation domain, leading to inactivation.
Using our novel methods to screen our proprietary stapled peptide library, we have identified a high-affinity peptide that binds the wild type estrogen receptor-α coactivation domain.
Regulating the Senescence-
Associated Secretory Phenotype (SASP)
Cellular senescence is characterized by irreversible cell cycle arrest and a proinflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Senescent cells accumulate during aging and negatively influence lifespan and promote age-dependent changes in several organs.
IL-1, IL-6, IL-8, TNF-α, TGF-β, and various matrix metalloproteinases (MMP3, 12) make up the key components of the SASP. The sustained inflammatory microenvironment created by the SASP can lead to chronic inflammation, which can have detrimental affects on tissues and organs, contributing to various age-related diseases and conditions. JAK kinases regulate the SASP through the JAK/STAT pathway. We are developing selective JAK2/3 topical TKIs as senomorphic therapy to down-regulate the SASP without the potential negative adverse effects of JAK1 inhibition.
