Abstract Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases.

10.1038/s41598-024-62804-7

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Prioritizing multiple therapeutic targets in parallel using automated DNA-encoded library screening

Nature Communications (2017)

Carl A. Machutta Christopher S. Kollmann Kenneth Lind Xiaopeng Bai Pan F. Chan

Abstract The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus . The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins. This concept was further explored by screening 42 targets from Mycobacterium tuberculosis . Active chemical series for six targets from our initial effort as well as three chemotypes for DHFR from M. tuberculosis are reported. The findings demonstrate that parallel ELT selections can be used to assess ligandability and highlight opportunities for successful lead and tool discovery.

10.1038/ncomms16081

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Additional file 15 of Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

Figshare (2022)

Mohammed Ghiboub Jan Köster Peter D. Craggs Andrew Y. F. Li Yim Anthony Shillings

Additional file 15: Table S15. Peptides location (Modified Histone Peptide Array).

Modulation (music)

10.6084/m9.figshare.20521114

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Modulation of macrophage inflammatory function through selective inhibition of the epigenetic reader protein SP140

BMC Biology (2022)

Mohammed Ghiboub Jan Köster Peter D. Craggs Andrew Y. F. Li Yim Anthony Shillings

Abstract Background SP140 is a bromodomain-containing protein expressed predominantly in immune cells. Genetic polymorphisms and epigenetic modifications in the SP140 locus have been linked to Crohn’s disease (CD), suggesting a role in inflammation. Results We report the development of the first small molecule SP140 inhibitor (GSK761) and utilize this to elucidate SP140 function in macrophages. We show that SP140 is highly expressed in CD mucosal macrophages and in in vitro - generated inflammatory macrophages. SP140 inhibition through GSK761 reduced monocyte-to-inflammatory macrophage differentiation and lipopolysaccharide (LPS)-induced inflammatory activation, while inducing the generation of CD206 + regulatory macrophages that were shown to associate with a therapeutic response to anti-TNF in CD patients. SP140 preferentially occupies transcriptional start sites in inflammatory macrophages, with enrichment at gene loci encoding pro-inflammatory cytokines/chemokines and inflammatory pathways. GSK761 specifically reduces SP140 chromatin binding and thereby expression of SP140-regulated genes. GSK761 inhibits the expression of cytokines, including TNF , by CD14 + macrophages isolated from CD intestinal mucosa. Conclusions This study identifies SP140 as a druggable epigenetic therapeutic target for CD.

Monocyte

Macrophage inflammatory protein

Proinflammatory cytokine

10.1186/s12915-022-01380-6

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Exploring the Value of Interdependence as Perceived by OT Practitioners

Lee Anna Bailey Kimberly A. Chambers Kimberly Knight Cynthia McCormack Heather P. O’Keefe

Value (mathematics)

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