G sub(s alpha )-selective G protein antagonists

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-01, Vol.95 (1), p.346-351
• Main Authors: Hohenegger, M, Waldhoer, M, Beindl, W, Boeing, B, Kreimeyer, A, Nickel, P, Nanoff, C, Freissmuth, M
• Format: Article
• Language: English
• ISSN: 0027-8424; 1091-6490

Suramin acts as a G protein inhibitor because it inhibits the rate-limiting step in activation of the G sub( alpha ) subunit, i.e., the exchange of GDP for GTP. Here, we have searched for analogues that are selective for G sub(s alpha ). Two compounds have been identified: NF449 (4,4',4',4''-[carbonyl-bis[imino-5,1,3-benzenetriyl bis-(carbonylimino)]]tetrakis-(benzene-1,3-disulfonate) and NF503 (4,4'-[carbonylbis[imino-3,1-phenylene-(2,5- benzimidazolylene)carbonylimino]]bis-benzenesulfonate). These compounds (i) suppress the association rate of guanosine 5'-[ gamma -thio]triphosphate ([ super(35)S]GTP[ gamma S]) binding to G sub(s alpha -s) but not to G sub(i alpha -1), (ii) inhibit stimulation of adenylyl cyclase activity in S49 cyc super(-) membranes (deficient in endogenous G sub(s alpha )) by exogenously added G sub(s alpha -s), and (iii) block the coupling of beta -adrenergic receptors to G sub(s) with half-maximum effects in the low micromolar range. In contrast to suramin, which is not selective, NF503 and NF449 disrupt the interaction of the A sub(1)-adenosine receptor with its cognate G proteins (G sub(i)/G sub(o)) at concentrations that are >30-fold higher than those required for uncoupling of beta -adrenergic receptor/G sub(s) tandems; similarly, the angiotensin II type-1 receptor (a prototypical G sub(q)-coupled receptor) is barely affected by the compounds. Thus, NF503 and NF449 fulfill essential criteria for G sub(s alpha )-selective antagonists. The observations demonstrate the feasibility of subtype-selective G protein inhibition.