Development of novel renin inhibitors and interaction of antimicrobial and cytotoxic peptides with plasma proteins. A drug discovery study

Abstract

In this study we have explored the structure activity relationship of molecules with potential as novel drug classes toward current medical challenges as hypertension, cancer and infections caused by antibiotic resistant bacteria. Direct renin inhibitors have for a long time been an interesting group of potential anti-hypertension drugs, as they inhibit the first and rate-limiting step in the signal peptide cascade that regulates blood pressure. We have found that substituted trans-3,4-disubstituted piperidine derivatives containing 1,4- or 1,5-disubstituted 1,2,3-triazoles are potent non-peptidomimetic inhibitors for renin. Antimicrobial and cytotoxic peptides based on natural host defense peptides from the innate immune systems of plants, insects and animals are a novel source of bioactive molecules. Drugs have to maintain their activity in a complex biochemical environment in vivo, and drug interactions with plasma proteins are known to affect the pharmacokinetics. The major plasma proteins affecting drug distribution are human serum albumin (HSA) and alpha-1 acid glycoprotein (AGP). We have shown that the peptides used in this study bind to drug site II of HSA with their hydrophobic moieties, and that this binding affects the activity in vitro. In our study with AGP, the binding was found to be of similar affinity compared with the HSA interaction, although the peptides were found to only interact with a fraction of AGP and did not affect the peptides´ in vitro performance. We suggest that HSA binding should be investigated routinely in antimicrobial and anticancer peptide development studies, as it will affect systemic distribution, whereas AGP binding is less likely to influence the activities in vivo.