C. MACK, A. GHAVAMI, B. CALDARONE, T. HANANIA, J. MALBERG, B. CHICCA, V. SRIVASTAVA, P. MCGONIGLE, W. ROTE, M. HANLEY, D. BRUNNER
Peptide hormones possess appealing drug profiles based on their role as natural integrators of physiological systems. As a result of our preclinical drug discovery efforts, we recently initiated clinical development of an analog of the peptide hormone amylin for the treatment of depression. Here we present preclinical evidence pointing to the therapeutic potential of peptides for the treatment of psychosis. Using PsychoGenics proprietary in vivo drug discovery technologies, which combine broad in vivo behavioral expertise with robotics and computer vision, we assessed the potential of a number of peptides for the treatment of psychosis in mice. The peptides tested originated from PHORMOL™, an extensive library of >1000 known and novel biologics which were obtained through public searches, or were bioinformatically or experimentally derived. Peptide 1 (PSN0484), and its analogs PSN0485, PSN0486, and PSN0487, displayed a strong antipsychotic behavioral signature in mice. Further testing in validated, preclinical models showed all peptides (1-3 mg/kg, IP) significantly attenuated phenylcyclidine (8 mg/kg, IP)-induced disruption of the acoustic startle response in mice. Importantly, there was no effect of any peptide on baseline startle response. In a second test of psychosis, mice administered PSN0484 and analogs (1mg/kg, IP) also reduced apomorphine (APO) -induced rearing and climbing. These data demonstrate positive effects of the Peptide 1 series in antipsychotic behavioral tests that are related to glutaminergic (PCP) and dopaminergic (APO) pathways, two major pathways involved in schizophrenia. Analogs from this series also exhibited acute cognitive enhancing effects in the novel object recognition test (0.3 and 1 mg/kg, IP) and produced weight loss with sustained 14-d SC infusion (10 ug/kg/d) in rats. Additional in vivo screening through PsychoGenics proprietary drug discovery technologies has identified Peptide 2 (PSN0240) and Peptide 3 (PSN0459) (3 and 6 mg/kg) as potential antipsychotic peptides, with PSN0459 also exhibiting modest mood stabilization activity. These data provide evidence for the potential of peptides for the treatment of psychosis, and demonstrate the superiority of the Peptide 1 series over marketed antipsychotic agents, the latter lacking efficacy in treating cognitive deficits and producing frank metabolic disturbances, including weight gain.