Patent ID: 7105488

Claim:
A method of inhibiting the biological activity of a target G protein-coupled receptor (GPCR) by contacting a cell that expresses said GPCR with an isolated GPCR-modulating molecule comprising a peptide that has at least five amino acids, an N-terminus and a C-terminus, said at least five amino acids being identical to the amino acid sequence of a portion of a transmembrane domain of said GPCR, wherein (a) said molecule has an extracellular end group that is negatively charged under physiological conditions, an intracellular end group with a neutral charge sufficient to allow insertion into a membrane under physiological conditions, and said molecule comprises the following modifications: when said intracellular end group is said C-terminus, said neutral charge includes a terminal carboxylamide group; or, when said intracellular end group is said N-terminus, said peptide or peptidomimetic includes at least four of the first five N-terminal amino acids having neutrally-charged amino acid side chains under physiologic conditions; and at least one of the end groups is a group that does not naturally occur at that position in the transmembrane sequence; (b) said molecule spontaneously inserts into a membrane in the same orientation as the transmembrane domain from which it is derived, wherein said molecule without the modifications in (a) does not spontaneously insert into the membrane in said orientation; and (c) said molecule inhibits a biological activity of said GPCR by disrupting the structure or assembly of said GPCR, wherein the biological activity is selected from the group consisting of signal transduction, binding of a virus and subsequent infection, tumor growth, chemotaxis, mitogenic response, cell growth activation, secretion, muscle contraction, vasopressing and vasodepressing activity, synaptic transmission, and release of intracellular calcium.