{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T20:47:12Z","timestamp":1785703632812,"version":"3.56.0"},"reference-count":57,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"LOEWE-GLUE initiative","award":["LOEWE\/2\/12\/519\/03\/05.001(0014)\/71"],"award-info":[{"award-number":["LOEWE\/2\/12\/519\/03\/05.001(0014)\/71"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:p>Orphan GPCRs of the GPRC5 family regulate macrophage activity and vascular contractility by dimerizing with other GPCRs, but pharmacological modulation of this process has not been explored. We previously identified the dimerization interface of receptor GPRC5B and show here that both its mutation and inhibition by a decoy peptide disturbed the interaction with the prostaglandin E2 receptor EP2 in macrophages, resulting in reduced EP2 signaling, enhanced migration and phagocytosis, and protection from bacterial peritonitis in mice. Furthermore, we show that a similar interface exists in related receptor GPRC5C, and, the same as in GPRC5B, mutation or inhibition by decoy peptide improved host defense. Through a virtual docking screen, we identified a small molecule inhibitor of both GPRC5B and GPRC5C dimerization, K303MP20, and showed that it reduced EP2 signaling, enhanced macrophage activity, and improved host defense in bacterial peritonitis and influenza A infection. Interestingly, K303MP20 not only blocked dimerization between GPRC5B\/C and EP2, but also with prostacyclin receptor IP and angiotensin II receptor AT1, resulting in reduced AT1-dependent contraction and enhanced IP-dependent relaxation in human and murine smooth muscle cells. In vivo, K303MP20 did not affect basal blood pressure, but protected mice from angiotensin II\u2013induced hypertension. Taken together, inhibition of orphan GPCR dimerization by small molecules is feasible and improves infection control and arterial hypertension.<\/jats:p>\n                  <jats:p>Pharmacological blockade of GPRC5B\/GPRC5C dimerization improves infection control and prevents arterial hypertension.<\/jats:p>","DOI":"10.1172\/jci203162","type":"journal-article","created":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T19:50:23Z","timestamp":1785700223000},"source":"Crossref","is-referenced-by-count":0,"title":["Small molecule inhibitor of orphan GPCR dimerization improves host defense and blood pressure control in mice"],"prefix":"10.1172","volume":"136","author":[{"given":"Jeonghyeon","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, 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