Site specific 1:1 opioid:albumin conjugate with in vitro activity and long in vivo duration.

A site-specific 1:1 dynorphin A-(1-13)-NH(2) derivative conjugated specifically to Cys 34 on human serum albumin (CCI-1035) was shown to be an opioid receptor agonist in vitro and to be a long lasting antinociceptive agent when administered intravenously to mice as assessed by an acetic acid writhing assay. When 10 micromol/kg of CCI-1035 was administered to mice, rapid antinociception was observed within 5 min following intravenous bolus injection and was sustained beyond 8 h. Antinociceptive activity was absent in a heat induced pain model using a mouse tail-flick assay. This finding represents the first report of a 1:1 albumin opioid conjugate retaining potent in vivo activity equal to or greater than dynorphin A, accompanied by a dramatic extension in duration of action. This novel site-specific bioconjugation technology produces an agent that may be useful for peripheral pain therapy.

Structural comparison of prostate-specific antigen and human glandular kallikrein using molecular modeling.

OBJECTIVES: Prostate-specific antigen (PSA), the most useful tumor marker for prostate cancer, is one of three members of the human kallikrein family of serine proteases. PSA and human glandular kallikrein (hK2, previously called hGK-1) share extensive homology and are both produced in the prostate under androgen control. Our goals were to use molecular modeling techniques to generate models of the tertiary structure of PSA and hK2 and to compare their molecular features and areas of homology using these models. METHODS: Models of PSA and hK2 were generated by extrapolating from available crystallographic coordinates and amino acid sequences of homologous members of the serine protease family using standard comparative methods. RESULTS: Porcine kallikrein (57% homology) and rat tonin (53% homology) were used as templates for PSA. Porcine kallikrein (67% homology) was used as a template for hK2. The models were superimposed to define regions of nonhomology between PSA and hK2. CONCLUSIONS: Three-dimensional protein models of PSA and hK2 were generated. These models have potential uses in analyzing antigen-antibody interactions, modeling of inhibitor complexes of both PSA and hK2, and furthering our understanding of the molecular interactions involved in the clinical detection of PSA and hK2.