1. Pharmacological interferences with the renin-angiotensin system
R E Lang, D Ganten, T Unger Arzneimittelforschung . 1984;34(10B):1391-8.
The important role of the renin-angiotensin system (RAS) in the maintenance of high blood pressure in certain forms of hypertension is well established. Inhibition of the RAS has therefore been studied with the aim to develop antihypertensive agents. Pharmacologic interferences with the RAS are possible at all steps of the formation, action and degradation of angiotensin II (ANG II). Renin activity can be inhibited by peptide analogues of angiotensinogen, peptides derived from the amino terminal sequence of pro-renin, inhibitors of acid proteases (pepstatin) and by specific renin antibodies. Inhibitors of the converting enzyme also prevent the formation of ANG II. ANG II receptor blockers (saralasin) prevent the action of the effector peptide of the RAS at the target cells. While some modes of intervention are still theoretical or experimental possibilities, others, e.g. inhibition of converting enzyme, are already used clinically for antihypertensive treatment.
2. Lower homologues of ahpatinin, aspartic protease inhibitors, from a marine Streptomyces sp
Kentaro Takada, Shigeru Okada, Shigeki Matsunaga, Yi Sun, Yuichi Nogi J Nat Prod . 2014 Jul 25;77(7):1749-52. doi: 10.1021/np500337m.
Two linear peptides, ahpatinin Ac (1) and ahpatinin Pr (2), were isolated together with the known ahpatinin (i)Bu, pepstatin Ac, pepstatin Pr, and pepsinostreptin from a Streptomyces sp. derived from a deep-sea sediment. The structure of ahpatinin Pr (2) was assigned by interpretation of NMR data and HPLC analysis of the hydrolysate after converting to the DNP-L-Val derivative. During the LCMS analysis of the acid hydrolysate, products arising from the retro-aldol cleavage of the statine and Ahppa units in 2 were observed and could facilitate the determination of the absolute configuration of the statine class of nonproteinogenic amino acids. Both ahpatinin Ac (1) and ahpatinin Pr (2) potently inhibited pepsin and moderately inhibited cathepsin B.
3. Pepstatin A: polymerization of an oligopeptide
P Traub, R L Shoeman, E Mothes Micron . 1994;25(2):189-217. doi: 10.1016/0968-4328(94)90042-6.
Pepstatin A, a pentapeptide with the molecular weight of 686, is a naturally occurring inhibitor of aspartyl proteases secreted by Streptomyces species. Above a critical concentration of 0.1 mM at low ionic strength and neutral pH, it can polymerize into filaments which may extend over several micrometers. After negative staining, these filaments show a helical substructure with characteristic diameters ranging from 6 to 12 nm. Selected images at higher magnification suggest the filaments are composed of two intertwined 6 nm strands. This is in agreement with the optical diffraction analysis which additionally established a periodic pitch of 25 nm for the helical intertwining. Rotary shadowing of the pepstatin A filaments clearly demonstrated the right-handedness of the helical twist. In physiological salt solution or at higher concentrations of pepstatin A, a variety of higher order structures were observed, including ribbons, sheets and cylinders with both regular and twisted or irregular geometries. Pepstatin A can interact with intermediate filament subunit proteins. These proteins possess a long, alpha-helical rod domain that forms coiled-coil dimers, which through both hydrophobic and ionic interactions form tetramers which, in turn, in the presence of physiological salt concentrations, polymerize into the 10 nm intermediate filaments. In the absence of salt, pepstatin A and intermediate filament proteins polymerize into long filaments with a rough surface and a diameter of 15-17 nm. This polymerization appears to be primarily driven by nonionic interactions between pepstatin A and polymerization-competent forms of intermediate filament proteins, resulting in a composite filament. Polymerization-incompetent proteolytic fragments of vimentin, lacking portions of the head and/or tail domain, failed to copolymerize with pepstatin A into long filaments under these conditions. These peptides, as well as bovine serum albumin, were found to stick to the surface of pepstatin A filaments, ribbons and sheets. Independent evidence for direct association of pepstatin A with intermediate filament subunit proteins was provided not only by electron microscopy but also by UV difference spectra. Pepstatin A loses its ability to inhibit the aspartyl protease of the human immunodeficiency virus type 1 following polymerization into the higher order structures described here. The amazing fact that pepstatin A can spontaneously self-associate to form very large polymers seems to be a more rare event for such small peptides. The other examples of synthetic or naturally occurring oligopeptides discussed in this review which are able to polymerize into higher order structures possess a common property, their hydrophobicity, often manifested by clusters of valine or isoleucine residues.(ABSTRACT TRUNCATED AT 400 WORDS)