Strategies to prolong the plasma residence time of peptide drugs

Peptides are an attractive class of molecules for the development of therapeutics because they combine unique properties such as high binding affinity, excellent target specificity, low toxicity and a relatively small mass. However, the short in vivo half-life of peptides which is typically only a few minutes had hampered the development of a larger number of peptide leads into drugs. The main reasons for the fast elimination of peptides from the circulation are enzymatic degradation and/or fast renal clearance. To prolong the half-life of peptides, their proteolytic stability can be improved by chemical modification strategies and the rate of clearance can be reduced by conjugating the peptides to molecules that prevent their elimination through the kidney. In this article we review the latter class of strategies that aims at prolonging the in vivo plasma residence time of peptides. Techniques including peptide drug linkage to large polymers, fusion to long-lived proteins such as albumin or the Fc fragment of immunoglobulin and conjugation to small molecule albumin-binding tags are discussed and the peptide-conjugate half-lives achieved are compared

Bicyclic Peptides Conjugated to an Albumin-Binding Tag Diffuse Efficiently into Solid Tumors

Monoclonal antibodies have long in vivo half-lives and reach high concentrations in tumors but cannot access all regions in the tissue, whereas smaller ligands such as peptides distribute better but are limited by low concentrations due to fast renal clearance. A potential solution to this problem might be offered by peptide-based ligands that are conjugated to an albumin-binding tag, and thus have a long plasma half-life. Herein, we tested if a small ligand based on a bicyclic peptide (1.9 kDa) conjugated to an albumin- binding peptide (2.3 kDa) can diffuse into tissues. Although the peptide conjugate (4.6 kDa) was most of the time bound to the large protein serum albumin (66.5 kDa), it diffused deeply into tissues and reached high nanomolar concentrations in wide areas of solid tumors. Most of the peptide conjugate isolated from tumor tissue was found to be fully intact 24 hours after administration. Because of its noncovalent interaction with albumin, the bicyclic peptide might dissociate to diffuse to tumor regions that are not accessible to larger ligands. Bicyclic peptides having high binding affinity for targets of interest and being proteolytically stable can be evolved by phage display; in conjunction with albumin-binding tags, they offer a promising format to access targets in solid tumors. (C) 2014 AACR

Measuring net protease activities in biological samples using selective peptidic inhibitors

The measurement of activities from individual proteases in biological samples is difficult because of the numerous proteases, their overlapping activities, and the lack of specific substrates. We applied selective protease inhibitors based on bicyclic peptides (>2000-fold selective over related proteases) to block individual proteases, allowing the quantification of their net activities. In protease mixtures, activity contributions of the serine proteases plasma kallikrein and urokinase-type plasminogen activator (uPA) were accurately quantified. In a tumor extract, we could quantify uPA activity. Because bicyclic peptide inhibitors toward virtually any protease can be generated by phage display, the approach should be applicable to any protease

P1–304: Arterial spin labeling cerebral blood flow and brain volumes in dementia‐free elderly

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152639/1/alzjjalz201305530.pd