Thomas J. Perun

Modified peptides which display potent and specific inhibition of human renin

A new class of angiotensinogen analogues which contain heteroatom-methylene and retro-inverso amide bond replacements was synthesized and evaluated for renin inhibition. Selected compounds in the series were specific for renin over other aspartic proteinases, and the most potent inhibitor demonstrated hypotensive activity in a salt depleted monkey.

Two-dimensional 1H NMR studies of rat atrial natriuretic factor(1–23)

Using a variety of two-dimensional NMR methods, the 1H NMR resonances of rat ANF(1-23) in dimethyl sulfoxide-d6 solution have been assigned. Two-dimensional phase sensitive correlated spectroscopy was used to identify protons that are scalar coupled and were also used to obtain coupling constants (3JNH-alpha CH) in complicated regions of the spectra. Relayed coherence transfer experiments proved useful in identifying the connectivities between the NH and beta-protons of the same amino acid residue. Finally, phase sensitive 2D NOE experiments allowed the identification of protons close in space between adjacent residues, thus providing the sequential assignments as well as conformational information. These preliminary results (chemical shifts, coupling constants, NOEs) were analyzed in terms of possible polypeptide secondary structures and were found to be consistent with a beta-type structure or an averaging of solution conformations (random coil).

Renin inhibitors Improvements in the stability and biological activity of small peptides containing novel Leu‐Val replacements

We have designed a novel class of potent (0.3–7 nM) renin inhibitors which contain a dihydroxyethylene replacement for what is formally the Leu1O‐Val11 amide bond. Good potency (0.6 nM), water solubility (> 10 mg/ml at 37°C), stability toward degradation by chymotrypsin (t =82O min), and in vivo activity in a primate model (15% drop in mean arterial pressure in association with complete inhibition of plasma renin activity) are properties which have been incorporated into compound 10, an interesting new agent to be used in the study of hypertension.

Peptide analogues of angiotensinogen effect of peptide chain length on renin inhibition

Renin inhibition was evaluated for a series of peptide analogues of angiotensinogen with different chain lengths. Systematic deletion of amino acid residues from the hexapeptide BocPheHisLeuR-ValIleHisOCH3 showed that the presence of residues at the N-terminal Phe and His positions was essential for efficient enzyme-inhibitor binding whereas the C-terminal Ile and His residues were much less important. Synthesis of a tetrapeptide analogue shortened at the C-terminus and containing modified side chains produced a potent inhibitor of renin which demonstrated hypotensive activity in a salt depleted monkey.