ABSTRACT
Inhibitors of the angiotensin converting enzyme (ACE, EC 3.4.15.1) are important in the treatment of the high blood pressure. The therapeutically used drugs captopril, enalapril and ramipril are enzymatic stable short pseudo-peptides. They are stabilized against enzymatic degradation and therefore usefully for oral application. But for some indications e.g. post operative treatment and shock therapy well dosed infusions are needed. For this purpose we attached nona-, penta- and tripeptide inhibitors of the ACE to immunologically inert dextran polymers. The inhibitors are derived as well from the bradykinin potentiating nonapeptide BPP9 alpha (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro) and the bradykinin potentiating pentapeptide BPP5 alpha (Pyr-Lys-Trp-Ala-Pro), both originally isolated from snake venoms, as from acylated tripeptides with the structure Acyl-AA1-Arg-Pro. We estimated the influence on the biological activity of two different linkers to the dextran polymers. The coupling to the polymer was achieved on the one hand via the aldehyd moiety (DAD-AK) and on the other hand by the carboxyl residue (KMD). In the case of DAD-AK-polymers the condensation of the peptides was performed by the N-hydroxysuccinimide ester of the polymer. Because of the instability of the KMD-OSU in this case water soluble carbodiimides are used. The polymer bound peptides inhibit the isolated ACE, but in the most cases with a reduced activity. Only the tripeptide DPhe-Arg-Pro has a enhanced activity in the polymer bound state. The polymer bound inhibitors show a prolongated action on normotensive rats by intravenous application.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Peptides/chemical synthesis , Amino Acid Sequence , Animals , Blood Pressure/drug effects , Dextrans , Male , Molecular Sequence Data , Peptides/pharmacology , Rats , Rats, Inbred StrainsABSTRACT
Inhibitors of the angiotensin-converting enzyme were synthesized by substituting N-and C-terminal amino acid residues of tripeptide Bz-Phe-Ala-Pro by the residues of 8-methoxy-5-sulphoquinoline and carboxy-1,2,3,4-tetrahydroquinoline, respectively, and their in vivo and in vitro biological activity was determined. The enzyme's S2' site proved to be non specific to the position of the carboxylic group in the C-terminal heterocyclic part of the inhibitor molecule. Introducing a modified quinoline residue into the N-terminal part of the inhibitor does not increase its specific interaction with the hydrophobic pocket of the angiotensin-converting enzyme.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/chemical synthesis , Quinolines/chemistry , Angiotensin-Converting Enzyme Inhibitors/metabolism , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Animals , Binding Sites , Captopril/pharmacology , Enalapril/pharmacology , Peptidyl-Dipeptidase A/metabolism , RatsABSTRACT
To investigate conformations of peptide inhibitors of the angiotensin-converting enzyme in the enzyme-inhibitor complex, the synthesis, studies of inhibitory activity, and conformational calculations of analogues of bradykinin-potentiating peptides with N-methylalanine or D-alanine in place of L-proline or L-alanine residues have been carried out. All the analogues showed a sharp decrease of inhibitory activity in comparison with the natural peptides, that might be considered as an indirect confirmation of the earlier proposed "conformation of inhibition" of the above-mentioned peptides.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Oligopeptides/chemical synthesis , Amino Acid Sequence , Chemical Phenomena , Chemistry, Physical , In Vitro Techniques , Models, Molecular , Oligopeptides/pharmacology , Protein ConformationABSTRACT
Affinity labeled analogues and partial sequences of the bradykinin potentiating nonapeptide BPP9 alpha inhibit the BPP9 alpha induced potentiation of the bradykinin action on the isolated guinea pig ileum. The labeled nonapeptides are more active than the labeled partial sequences. The inhibition of the potentiating action of BPP9 alpha demonstrates, that the influence on bradykinin action is not only a result of the inhibition of peptidyl dipeptide hydrolase.
Subject(s)
Bradykinin/pharmacology , Oligopeptides/chemical synthesis , Teprotide/chemical synthesis , Affinity Labels/chemical synthesis , Animals , Chemical Phenomena , Chemistry , Drug Synergism , Guinea Pigs , In Vitro Techniques , Kinetics , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Protease Inhibitors , Teprotide/pharmacologyABSTRACT
The synthesis of 5 analogues of the effective inhibitor of peptidyl dipeptidase, teprotide, has been carried out. The inhibitory and bradykinin-potentiating activity of these compounds has been assayed. N-Terminal pyroglutamic acid and positive charge of arginine in position 4 were found to be essential for biological activity of the inhibitor.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors , Oligopeptides/chemical synthesis , Teprotide/chemical synthesis , Amino Acid Sequence , Animals , Bradykinin/pharmacology , Chemical Phenomena , Chemistry , Circular Dichroism , Drug Synergism , Guinea Pigs , Ileum/drug effects , In Vitro Techniques , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Protein Conformation , Teprotide/analogs & derivatives , Teprotide/pharmacologyABSTRACT
Properties of the carboxycathepsin inhibitors teprotide, captopryl, enalacryl are considered. Presence of low molecular thermo- and acid stable carboxycathepsin inhibitors of peptide nature in blood serum and lymphocytes is discussed.
