The Medicinal Chemistry of Peptides

Abstract

The shortcomings of native peptides as pharmaceuticals have been long known: short duration of action, lack of receptor selectivity, lack of oral bioavailability. However medicinal chemistry offers solutions to the first two limitations and oral bioavailability issues have been addressed with novel routes of administration (e.g. intranasal, inhalation) and injectable depot formulations. The principal issue for peptide drugs has been a short duration of action, widely assumed to be due to proteolysis. While proteolysis is a problem for native peptide structures, modification of the peptide structure by acylation, PEGylation, unnatural amino acids or restricted conformation can largely remove this issue. However rapid clearance from the blood into the urine remains an issue for even proteolytically stable molecules. Medicinal chemistry approaches here have been peptide modifications to slow release from the injection site (hydrophobic, hydrophilic, self-associating depots), PEGylation, fatty acid acylation, and the like. Medicinal chemistry approaches used in successful peptide pharmaceuticals using unnatural amino acids to achieve depot formation are highlighted in this review.

Antihypertensive Properties of Plant Protein Derived Peptides

“…Anyhow, it seems that no general strategy for improving bioavailability of antihypertensive peptides exists and due to the number of processes involved and different characteristics of peptides depending on the sequence each case must be studied. Many strategies are currently demonstrated for enhancing bioavailability [171], among them microencapsulation for controlled release of the active compounds, stabilization of the active molecules to improve transportation through the intestinal barrier and provide resistance against degradation, and development of highly stabile peptide analogues [172][173][174].…”

Prediction and interpretation of the lipophilicity of small peptides

“…log D oct is in fact of the utmost relevance in ADME-Tox studies [7]. For instance the determination of log D oct is expected to be really important in the prediction of the hydrophobic depoting of peptides (a strategy to prevent too fast renal clearance) and in the description of peptide cellular uptake [8]. Brain-targeted peptide delivery is also strongly dependent on lipophilicity [9].…”

Peptides and Peptidomimetics in Medicinal Chemistry

“…and as functional excipients in drug delivery systems to overcome tissue and cellular membrane barriers (Nestor, 2009). From a pharmaceutical point of view, peptides are situated somewhere between classical organic drug substances and high molecular weight biopharmaceuticals.…”

“…However medicinal chemistry offers solutions to the first two limitations and oral bioavailability issues have been addressed by novel routes of administration (e.g. intranasal, inhalation) and injectable depot formulations (Nestor, 2009). …”