Research ArticlePharmacology

G protein subtype–specific signaling bias in a series of CCR5 chemokine analogs

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Science Signaling  16 Oct 2018:
Vol. 11, Issue 552, eaao6152
DOI: 10.1126/scisignal.aao6152

Biasing CCR5 against inflammation

The G protein–coupled chemokine receptor CCR5 is required for the cellular entry of HIV-1. The ideal drug targeting CCR5 to block HIV-1 infection would induce receptor internalization without triggering the undesirable effect of inflammation. Thus, Lorenzen et al. characterized the signaling properties of two endogenous ligands of CCR5, RANTES and MIP-1α, and several RANTES analogs in cells expressing CCR5 with Gi/o or Gq/11 subunits. They found that CCR5 inhibited generation of the second messenger cAMP by stimulating Gi/o and induced Ca2+ signaling through Gq/11 and that the RANTES analogs differentially activated Gi/o and Gq/11. The authors hypothesize that RANTES analogs that preferentially stimulate Gi/o may block HIV-1 infection without inducing inflammation.

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