Inhibition of angiotensin-converting enzyme by analogs of peptides fromBothrops jararaca venom

Cushman, David; Pluščec, Jelka; Williams, Nina J.; Weaver, Eugene R.; Sabo, Emily F.; Kocy, O.; Cheung, H.S.; Ondetti, Miguel A.

doi:10.1007/bf01930447

Cited by 96 publications

(54 citation statements)

References 34 publications

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“…The terminal sequence TrpAla-Pro of BPP 5a , or the related but more stable sequence Phe-Ala-Pro, was found to be optimal for binding to the active site of ACE. These important structure-activity studies were published jointly, 7 as were nearly all subsequent papers during the next decade, a clear indication that a true state of collaboration had been achieved. But none of this yet was drug design.…”

Section: History Of the Design Of Captopril And Related Inhibitors Ofmentioning

confidence: 90%

History of the design of captopril and related inhibitors of angiotensin converting enzyme.

1991

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Section: History Of the Design Of Captopril And Related Inhibitors Ofmentioning

confidence: 90%

History of the design of captopril and related inhibitors of angiotensin converting enzyme.

1991

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“…In addition, the elucidated structures could assist pharmaceutical companies to develop potent drugs whereby the identified peptide sequences serve as molecular templates. This is highly relevant because the development of the first pharmaceutically successful antihypertensive drug (captopril) was based on the molecular templates of snake venom peptides (Cushman et al, 1973;Cushman, Cheung, Sabo, & Ondetti, 1977).…”

Section: List Of Tables Pagementioning

confidence: 99%

Structural and functional characterization of hemp seed (Cannabis sativa L.) protein-derived antioxidant and antihypertensive peptides

Girgih

Malomo

et al. 2014

Journal of Functional Foods

243

142

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The aim of this work was to produce enzymatic hemp seed protein hydrolysates (HPH) followed by bioassay guided fractionation to identify antioxidant and antihypertensive peptides. Therefore, simulated gastrointestinal digestion of isolated hemp seed proteins was conducted using consecutive actions of pepsin and pancreatin to produce HPH, which was then separated by membrane ultrafiltration to obtain peptide sizes of <1, 1-3, 3-5, and 5-10 kDa. Evaluation of HPH and its membrane fractions for antioxidant and antihypertensive properties showed that they significantly (P<0.05) scavenged radicals, reduced and strongly chelated metal ions as well as inhibited lipid oxidation. During a 24-hr test, the HPH reduced systolic blood pressure (SBP) of spontaneously hypertensive rats (SHR) after oral administration by a maximum of -30 mmHg when compared to -15 mmHg for the membrane fractions.To reduce production cost, hemp seed protein meal (HPM) was directly hydrolyzed to a protein hydrolysate (HMH) and was shown to also reduce SBP during 4-8 weeks of dietary feeding. The attenuation of SBP correlated to suppressed plasma levels (0.047-0.059 U/mL and 0.040-0.054 µg/mL) of angiotensin converting enzyme (ACE) and renin, respectively, when compared to the control rats (0.123 U/mL and 0.151 µg/mL). A total of 23 peptides were identified to be present in the HPH. WVYY and PSLPA showed superior in vitro antioxidant properties, while ACE activity was inhibited by WYT (89%), WVYY (91%) and PSLPA (90%). Renin activity was inhibited by WYT (77%), SVYT (87%) and IPAGV (75%). However, oral administration to SHR showed that the pentapeptides (PSLPA and IPAGV) were more effective SBP-reducing agents (-40 mm Hg) when compared to the tri-(-13 mmHg) and tetrapeptides (-36 mmHg). These results

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“…So esters were chosen that might build back potency through added binding in the enzyme's S, subsite. We elected to examine esters containing a phenyl ring because of the analogies with Phe-Ala-Pro and other good peptide inhibitors containing aromatic amino acids at the antepenultimate position (21). The importance of having a P-OH function is revealed by diester 8 which has considerably less activity than the monoester 6.…”

Section: Resultsmentioning

confidence: 99%

“…The crude benzyl 2-methyl-3-phosphonylpropionyl-L-prolinate was purified over Dowex 50 (H', H20 elution). The acidic fractions were combined and the product was chromatographed over XAD-2 resin (CH3CN/H20/HOAc, 21 Benzyl Dibenzylphospho-L-alanyl-L-prolinate. This triester was synthesized by using procedures described by Kam et aL (12).…”

mentioning

confidence: 99%

Phosphorus-containing inhibitors of angiotensin-converting enzyme.

Thorsett¹,

Harris²,

Peterson³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

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Several phosphonamides, phosphoramides, and phosphates having the general structure R-Y-P(OXOH-X-CH(CHl)-CO-Pro have been synthesized and tested for inhibition of angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyldipeptide hydrolase, EC 3.4.15.1). Inhibition was found to depend on the nature of R, Y, and X such that the maximal effect was observed when X = NH, Y = CH2, and R = 4CH2 (50% inhibition at 7 nM). Substitution of CH2 or 0 at X and 0 at Y produced significantly less potent inhibitors. Groups shorter or longer than R = 4CH2 led to less active inhibitors, presumably due to nonoptimal interaction of the side chain with the SI subsite.Angiotensin-converting enzyme (dipeptidyl carboxypeptidase; peptidyldipeptide hydrolase, EC 3.4.15.1) cleaves angiotensin I to the potent vasopressor angiotensin II. It also inactivates the vasodepressor substance bradykinin. The possibility that inhibitors of the enzyme might have clinical importance in the treatment of hypertension has been demonstrated with teprotide (1-3) and more recently by extensive clinical studies using the orally active angiotensin-converting enzyme inhibitor captopril (4). Accordingly, there is much current interest in the synthesis of inhibitors of the enzyme (5, 6).Like thermolysin and carboxypeptidases A and B, angiotensin-converting enzyme contains a zinc atom in its active site (7) that, by analogy, is intimately involved in the cleavage of the scissile carboxamide bond of its substrates. Phosphoramidon (ref. 12 and references cited therein) has shown that the inhibition of metalloproteases by phosphorus compounds may be quite general. Indeed, Holmquist and Vallee (13) recently reported inhibition of angiotensin-converting enzyme by several phosphoramidates, including monophenylphospho-L-phenylalanyl-L-phenylalanine, which exhibited Ki = 1.0 uM. Galardy (14) has reported that phospho-L-alanyl-L-proline is a potent inhibitor of the enzyme and exhibited a Ki of 1.4 nM at pH 7.5.The compounds we shall describe are derivatives of the general structure I. In analogy with the binding ofphosphoramidon to thermolysin, substructure lB is proposed to position itself at the zinc site of the enzyme and to approximate the geometry of a hydrated amide transition state. Substructure UI should then be able to bind in the S, subsite of angiotensin-converting enzyme and corresponds to the R1 substitution so important in the recently described (15) N-carboxymethyldipeptide inhibitors of the enzyme. Substructure IC was chosen because 2-substituted propanoylproline derivatives had been shown to afford very potent inhibitors of angiotensin-converting enzyme (15, 16).MATERIALS AND METHODS A description of our assay procedure has been published (15).2-Methyl-3-phosphonylpropionyl-L-proline (1). d,l-2-Methyl-3-phosphonylpropionic acid (6 g) was stirred with SOC12 (100 ml) overnight at room temperature. Concentration afforded the carboxyl chloride, which was coupled to benzyl L-prolinate hydrochloride (8.4 g) in aqueous dioxane under Sch...

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Inhibition of angiotensin-converting enzyme by analogs of peptides fromBothrops jararaca venom

Cited by 96 publications

References 34 publications

History of the design of captopril and related inhibitors of angiotensin converting enzyme.

History of the design of captopril and related inhibitors of angiotensin converting enzyme.

Structural and functional characterization of hemp seed (Cannabis sativa L.) protein-derived antioxidant and antihypertensive peptides

Phosphorus-containing inhibitors of angiotensin-converting enzyme.

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