Biology subjects

Joy, S. T.

Publications and source records attributed to Joy, S. T..

3 recordsLinked to original sources

bioRxiv2023

Inhibition of the melanocortin-3 receptor (MC3R) causes generalized sensitization to anorectic agents

The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to other agents, including the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor, leptin, demonstrated that increased sensitivity to anorectic agents is a generalized result of MC3R antagonism. Enhanced neuronal activation in multiple nuclei, including ARH, VMH, and DMH, was observed using Fos immunohistochemistry following low-dose liraglutide in MC3R knockout mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits regulating multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r -/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1R analogs, suggesting that MC3R antagonists may have value in enhancing the dose-response range of obesity therapeutics.

neuroscience↗

bioRxiv2023

Inhibition of CREB binding and function with a dual-targeting ligand

CBP/p300 is a master transcriptional coactivator, regulating gene activation by interacting with multiple transcriptional activators. Dysregulation of protein-protein interactions (PPIs) between the CBP/p300 KIX domain and its activators is implicated in a number of cancers including breast, leukemia, and colorectal cancer. However, KIX is typically considered undruggable because of its shallow binding surfaces lacking both significant topology and promiscuous binding profiles. We previously reported a dual-targeting peptide (MybLL-tide) that inhibits the KIX-Myb interaction with excellent specificity and potency. Here we demonstrate a branched, second-generation analog, CREBLL-tide, that inhibits the KIX-CREB PPI with higher potency and selectivity. Additionally, the best of these CREBLL-tide analogs shows excellent and selective anti-proliferation activity in breast cancer cells. These results indicate CREBLL-tide is an effective tool for assessing the role of KIX-activator interactions in breast cancer and expanding the dual-targeting strategy for inhibiting KIX and other coactivators that contain multiple binding surfaces.

biochemistry↗

bioRxiv2021

A Dual-Site Inhibitor of CBP/p300 KIX is a Selective and Effective Modulator of Myb

The protein-protein interaction between the KIX motif of the transcriptional coactivator CBP/p300 and the transcriptional activator Myb is a high value target due to its established role in certain acute myeloid leukemias (AML) and potential contributions to other cancers. However, the CBP/p300 KIX domain has multiple binding sites, several structural homologues, many binding partners, and substantial conformational plasticity, making it challenging to specifically target using small molecule inhibitors. Here, we report a picomolar dual-site inhibitor (MybLL-tide) of the Myb-CBP/p300 KIX interaction. MybLL-tide has higher affinity for CBP/p300 KIX than any previously reported compounds while also possessing 16,000-fold selectivity for the CBP/p300 KIX domain over other coactivator domains. MybLL-tide blocks the association of CBP and p300 with Myb in the context of the proteome leading to inhibition of key Myb*KIX-dependent genes in AML cells. These results show that MybLL-tide is an effective, modifiable tool to selectively target the KIX domain and assess transcriptional effects in AML cells and potentially other cancers featuring aberrant Myb behavior. Additionally, the dual-site design has applicability to the other challenging coactivators that bear multiple binding surfaces

biochemistry↗