Extending apo-sGC to haem-sensing proteins and a landscape of haem mimetic pharmacophores with broad applications

• DOI: 10.14293/cgmp.24000016.v1
• Publication Date: 2024-06-05T17:13:10Z
• Authors: Mahmoud H. Elbatreek; Ruma Banerjee; Alexandra Petraina; Victor Vitvitsky; Thomas P. Burris; Vu Thao-Vi Dao; Stefan H. Heinemann; Toshinori Hoshi; Mahdi Jamili; Thomas Koelblen; Theodora Saridaki; Roland Schönherr; Wolfgang Sippl; Csaba Szabo; Yutao Tian; Aurore Valfort; Tianyuan Wang; Li Zhang; Karim Zuhra; Harald H. H. W. S...

<p class="first" dir="auto" id="d1176686e339">Haem, a fundamental prosthetic group, mediates oxygen transport and metabolism in proteins while exerting signalling functions haemolytic disorders through its pro-oxidant, pro-inflammatory, cytotoxic effects when unbound. In addition to established functions, haem plays crucial role regulating haem-responsive such as apo-soluble guanylate cyclase (apo-sGC) the REV-ERB nuclear receptors, both of which are targets for clinical drug development. Through comprehensive series vitro assays involving apo-sGC, REV-ERB, four other haem-sensing proteins—Slo1/BK potassium channel, cystathionin-β-synthase, Gis1 transcription factor, hNaV1.5 sodium channel—we discovered unexpected interactions between apo-sGC activators, traditionally developed cardiovascular pulmonary conditions, along with most tested proteins. Heme concentration dynamics were unaffected. Conversely, ligands, designed initially address sleep metabolic syndromes, influenced activity. This investigation significantly broadens our understanding pharmacological implications mimetics, highlighting importance integrating protein into profiling class mimetic pharmacophores activators modulators mitigate potential off-target adverse reactions.