Identification of a novel opioid peptide (Tyr-Val-Pro-Phe-Pro) derived from human alpha(S1) casein (alpha(S1)-casomorphin, and alpha(S1)-casomorphin amide)

A new casomorphin pentapeptide (alpha(S1)-casomorphin) has been isolated from the sequence of human alpha(S1)-casein [alpha(S1)-casein-(158-162)], with the sequence Tyr-Val-Pro-Phe-Pro. This peptide was found to bind with high affinity to all three subtypes of the kappa-opioid receptor (kappa(1)-kappa(3)). When amidated at the C-terminus, alpha(S1)-casomorphin amide binds to the delta- and kappa(3)-opioid sites. Both alpha(S1)-casomorphin and its amide inhibit in a dose-dependent and reversible manner the proliferation of T47D human breast cancer cells. This anti-proliferative activity was greater for alpha(S1)-casomorphin, which was the most potent opioid in inhibiting T47D cell proliferation. In T47D breast cancer cells, other casomorphins have been found to bind to somatostatin receptors in addition to opioid sites. In contrast, alpha(S1)-casomorphin and its amide do not interact with somatostatin receptors in our system.