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Background: Oratosquilla woodmasoni is one of the marine squilla species, which is found in the entire Asia-Pacific region. This current study assesses the species as the main basis of both ACEi and antioxidant peptide., Objective: To isolate the ACEi peptide derived from O. woodmasoni and examine its ACE inhibition along with antioxidant potential., Materials and Methods: The squilla muscle protein was hydrolysed using alcalase and trypsin enzymes for 12 hours and tested for DH. The hydrolysates were examined for their ACEi activity and then the best hydrolysate was sequentially purified in various chromatographical methods. The purified peptide was studied for anti-oxidant and functional properties, followed by amino acid sequencing. The purified peptide was also evaluated for its toxicity by in vitro cell viability assay., Results: The DH% was found to be 47.13 ± 0.72% and 89.43 ± 2.06% for alcalase and trypsin, respectively. The alcalase 5th-hour hydrolysate was detected with potent activity (65.97 ± 0.56%) using ACEi assay and was primarily fractionated using ultrafiltration; the maximum inhibitory activity was found with 77.04 ± 0.52% in 3-10 kDa fraction. Subsequently, the fraction was purified using IEC and GFC, in which the AC1-A2 fraction had higher antihypertensive activity (70.85 ± 0.78%). The non-toxic fraction showed hexapeptide HVGGCG with molecular weight 529 Da with great potential of antioxidant activity along with functional property., Conclusion: This peptide could be developed as a potential ACE-inhibitory and antioxidant agent., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The two-domain dipeptidylcarboxypeptidase Angiotensin-I-converting enzyme (EC 3.4.15.1; ACE) plays an important physiological role in blood pressure regulation via the reninangiotensin and kallikrein-kinin systems by converting angiotensin I to the potent vasoconstrictor angiotensin II, and by cleaving a number of other substrates including the vasodilator bradykinin and the anti-inflammatory peptide N-acetyl-SDKP. Therefore, the design of ACE inhibitors is within the priorities of modern medical sciences for treating hypertension, heart failures, myocardial infarction, and other related diseases. Despite the success of ACE inhibitors for the treatment of hypertension and congestive heart failure, they have some adverse effects, which could be attenuated by selective domain inhibition. Crystal structures of both ACE domains (nACE and cACE) reported over the last decades could facilitate the rational drug design of selective inhibitors. In this review, we refer to the history of the discovery of ACE inhibitors, which has been strongly related to the development of molecular modeling methods. We stated that the design of novel selective ACE inhibitors is a challenge for current researchers which requires a thorough understanding of the structure of both ACE domains and the help of molecular modeling methodologies. Finally, we performed a theoretical design of potential selective derivatives of trandolaprilat, a drug approved to treat critical conditions of hypertension, to illustrate how to use molecular modeling methods such as de novo design, docking, Molecular Dynamics (MD) simulations, and free energy calculations for creating novel potential drugs with specific interactions inside nACE and cACE binding sites., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Drug-protein complexes is one of the crucial factors when analyzing the pharmacokinetics and pharmacodynamics of a drug because they can affect the excretion, distribution, metabolism and interaction with target tissues., Objectives: The aim of this study was to investigate the interaction of human hemoglobin (Hb) and angiotensin I converting enzyme inhibitory peptide (ACEIP) in the absence and presence of different- frequency electromagnetic fields (EMF)., Methods: Various spectroscopic methods like fluorescence spectroscopy, ultraviolet, circular dichroism and conductometry techniques were applied to investigate Hb-ACEIP interaction in the absence and presence of EMF., Result: The presented spectroscopic studies indicated that EMF changed the interaction between Hb and ACEIP. The a-helix content of Hb decreased upon binding to ACEIP and conductivity of the solution enhanced upon binding. Based on Stern-Volmer equations, it could be stated that the Hb-ACEIP affinity was higher in the presence of EMF., Conclusion: It can be concluded that for patients who use the drug to control blood pressure, a low-frequency electromagnetic field would have a positive effect on the uptake of the drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity., Objective: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system., Methods: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction., Results: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively., Conclusion: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The Angiotensin-I converting enzyme (ACE) is one of the most important components of the renin-angiotensin-aldosterone system controlling blood pressure and renal functions. Inhibitors of ACE are first line therapeutics used in the treatment of hypertension and related cardiovascular diseases. Somatic ACE consists of two homologous catalytic domains, the C- and N-domains. Recent findings have shown that although both domains are highly homologous in structure, they may have different physiological functions. The C-domain is primarily involved in the control of blood pressure, in contrast to the N-domain that is engaged in the regulation of hematopoietic stem cell proliferation. The currently available ACE inhibitors have some adverse effects that can be attributed to the non-selective inhibition of both domains. In addition, specific Ndomain inhibitors have emerged as potential antifibrotic drugs. Therefore, ACE is still an important drug target for the development of novel domain-selective drugs not only for the cardiovascular system but also for other systems., Objective: Detailed structural information about interactions in the protein-ligand complex is crucial for rational drug design. This review highlights the structural information available from crystallographic data which is essential for the development of domain selective inhibitors of ACE., Methods: Over eighty crystal complexes of ACE are placed into the Protein Database. An overview of X-ray ACE complexes with various inhibitors in C- and N-domains and an analysis of their binding mode have given mechanistic explanation of the structural determinants of selective ligand binding. In addition, ACE domain selective inhibitors with dual modes of action in complexes with ACE are also discussed., Conclusion: Selectivity of ACE inhibitors for the N- and C-domain is controlled by subtle differences in the amino-acids forming the active site. Reported studies of crystal complexes of inhibitors in the C- and N-domains revealed that most selective inhibitors interact with non-conserved amino-acids between domains and have distinct interactions with the residues in the S2 and S2' subsites of the ACE catalytic site. Moreover, unusual binding of the second molecule of inhibitors in the binding cavity opens new possibilities of exploiting more distant regions of the catalytic center in structure-based design of novel drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated., Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic., Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 µg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril., Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Local classification models were used to establish Quantitative Structure- Activity Relationships (QSARs) of bioactive di-, tri- and tetrapeptides, with their capacity to inhibit Angiotensin Converting Enzyme (ACE). These discrete models can thus predict this activity for other peptides obtained from functional foods. These types of peptides allow some foods to be considered nutraceuticals., Method: A database of 313 molecules of di-, tri- and tetrapeptides was investigated and antihypertensive activities of peptides, expressed as log (1/IC50), were separated into two qualitative classes: low activity (inactive) was associated with experimental values under the 66th percentile and active peptides with values above this threshold. Chemicals were divided into a training set, including 70% of the peptides, and a test set for external validation. Genetic algorithms-variable subset selection coupled with the kNN and N3 local classifiers were applied to select the best subset of molecular descriptors from a pool of 953 Dragon descriptors. Both models were validated on the test peptides., Results: The N3 model turned out to be superior to the kNN model when the classification focused on identifying the most active peptides., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The Renin-Angiotensin System (RAS) has emerged as being related to vascular disease. Recently the RAS has been associated with obesity, diabetes, and even cancer., Objective: This review and Bioinformatics analyses focuses on the investigation of Angiotensinconverting enzymes (ACE and ACE2) as therapeutical targets for Malignant Epithelial Neoplasia, specifically for Oral Squamous Cell Carcinoma (OSCC)., Conclusion: The literature review and Bioinformatics analyses showed that ACE and ACE2 are interesting targets for OSCC treatment. Studies involving RAS and OSCC should be encouraged for experimental validation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Snake venoms are natural sources of biologically active molecules that are able to act selectively and specifically on different cellular targets, modulating physiological functions. Thus, these mixtures, composed mainly of proteins and peptides, provide ample and challenging opportunities and a diversified molecular architecture to design and develop tools and agents of scientific and therapeutic interest. Among these components, peptides and small proteins play diverse roles in numerous physiological processes, exerting a wide range of pharmacological activities, such as antimicrobial, antihypertensive, analgesic, antitumor, analgesic, among others. The pharmaceutical and cosmetic industries have recognized the huge potential of these privileged frameworks and believe them to be a promising alternative to contemporary drugs. A number of natural or synthetic peptides from snake venoms have already found preclinical or clinical applications for the treatment of pain, hypertension, cardiovascular diseases and aging skin. A well-known example is captopril, whose natural peptide precursor was isolated from Bothrops jararaca snake venom, which is a peptide-based drug that inhibits the angiotensin-converting enzyme, producing an anti-hypertensive effect. The present review looks at the main peptides (natriuretic peptides, bradykinin-potentiating peptides and sarafotoxins) and low mass proteins (crotamine, disintegrins and three-Finger toxins) from snake venoms, as well as synthetic peptides inspired by them, describing their biochemical, structural and physiological features, as well as their applications as research tools and therapeutic agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Carp muscle tissue is a valuable source of biologically active constituents known to positively influence human health. In this study, carp protein digests/hydrolysates generated by human/ porcine digestive enzymes were analysed for their angiotensin I-converting enzyme inhibitory (ACEi) activity. The ex vivo digests and in vitro hydrolysates were used in a screening for ACEi peptides as well. Carp proteins were hydrolysed more rapidly by human gastrointestinal juices than by porcine enzymes. Sarcoplasmic protein fractions were digested/hydrolysed more easily than the myofibrillar ones. The inhibitory concentrations at 50% (IC50) for ex vivo digested sarcoplasmic and myofibrillar protein fractions were established at 1.50 and 1.04 mg/mL, respectively. While, for in vitro hydrolysed sarcoplasmic and myofibrillar protein fractions, the IC50 values were calculated as 2.57 and 1.12 mg/mL, respectively. The digested/hydrolysed samples of carp sarcoplasmic and myofibrillar protein fractions were separated by RP-HPLC-MS. Amino acid sequences were identified with the use of the LC-MS/MS method coupled with in silico systematic screening for ACEi peptides. ACEi peptides with IVY, IY, VY, ALPHA and VKAGF sequences were found in the carp digests/hydrolysates. In the ex vivo carp digest, an ACEi peptide TVY was also detected, while the ACEi peptide IW was identified in in vitro hydrolysate. Our study showed that different ACEi effects of carp digests and hydrolysates were generated with the use of human gastrointestinal and porcine enzymes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Collagen, a predominant structural protein in extracellular matrix (ECM), is now considered to have probable roles in many biological activities and hence, in different forms have found application as nutraceutical or pharmaceutical therapy option. Many of the biological properties are believed to be due to small hidden peptide residues in the collagen molecules, which come into play after the biodegradation or biosorption of the parent molecule. These peptide regions are called cryptic peptides or by some, as cryptides. The proteolytic hydrolysis of the ECM protein releases the cryptic peptides with many novel biological activities not exhibited directly by the parental protein which include angiogenic, antimicrobial, mitogenic and chemotactic properties. The research for understanding the role of these cryptic peptide regions and making use of them in medical field is very active. Such an understanding could lead to the development of peptide supplements for many biomedical applications. The prolific research in this area is reviewed in this paper.

The renin-angiotensin system has been established as an attractive target for pharmacological intervention since the discovery of first angiotensin-converting enzyme inhibitors (ACE-Is). In fact, these drugs are primarily used in the management of cardiovascular system-related diseases and renal insufficiency. Their mechanism of action involves the adjustment of balance between vasoconstrictive, hypertrophic and salt/water-retentive angiotensin II and vasodilatory and natriuretic bradykinin by the inhibition of angiotensin II biosynthesis and bradykinin degradation. Currently there are thirteen family members approved for use in humans. They differ in structure, chemistry and pharmacokinetic and pharmacodynamic properties yet they display a similar pharmacologic and toxicologic profile. All of them are effective in the treatment of hypertension as well as in cardiac insufficiency or diabetic nephropathy. Although they are generally well-tolerated several serious side-effects including life-threatening angioedema, renal failure and persistent dry cough could occur during the administration of ACE-Is, which may require the cessation of therapy. Furthermore, to provide maximum safety and efficiency of ACE-Is-based therapy, the knowledge of the related drug interactions and chronokinetics seems to be an absolute requirement. Here we discuss the above-mentioned issues regarding the pharmaceutical and chemical properties of the commercially- used ACE-Is.

The gastroretentive drug delivery system is site-specific and allows the drug to remain in the stomach for a prolonged period of time so that it can be released in a controlled manner in gastrointestinal tract. The present study was carried out to develop a gastroretentive drug delivery system using isabgol as an excipient to prolong the residence time of the model drug lisinopril in the stomach. The gastroretentive ability of isabgol was increased by addition of NaHCO3 as a gas-generating agent while its mucoadhesive property was enhanced by incorporation of HPMC-K4M. The drug, NaHCO3 and HPMC-K3M were imbibed on isabgol-husk as per entrapment efficiency of the isabgol-husk. After drying, the product was filled in a hard gelatin capsule and evaluated for its buoyancy, mucoadhesive properties, swelling index and in vitro drug release. The lisinopril released through isabgol was delayed by 12 hours when compared to a preparation available on the market which released the complete drug in 0.5 hours. The drug release study of lisinopril from the formulation follows first order kinetics using a diffusion controlled mechanism. The results from the present study revealed that isabgol can be used as a potential excipient for the formulation of gastroretentive drug delivery systems in the near future.

Among bioactive peptides derived from aquatic protein, those with ACE inhibitory activity are receiving special attention. This paper presented an overview of ACE inhibitory peptides derived from aquatic proteins, and the peptide sources were listed. The structure-activity relationship and mechanism of action of ACE inhibitory peptides were also discussed. Finally, the antihypertensive effects of ACE inhibitory peptides derived from marine protein, including short-term and long-term influence, were also discussed.

The human angiontensin-converting enzyme I (hACEI) is a zinc metalloproteinase that hydrolytically cleaves a C-terminal dipeptide from a wide range of peptide substrates, and it plays an important role in regulating blood pressure. MD simulations and interaction energy calculations for docking and crystal structures were performed to investigate the correct conformation of the ACE with enalaprilat and nanopepetide. The analysis of root-mean-squrared fluctuation (RMSF), which is usually applied to measure the mobility and flexibility of the proteins, and dynamic correlation of residues show that the fluctuation pattern of the each two structure of the same ligand is almost the same mode. Hydrogen bond analysis shows that the correct crystal conformation is more stable than a wrong docking conformation. In addition, we are demonstrating that calculating interaction energy between protein and its ligands is an accurate and efficient way to select the correct conformation from docking conformations.

Although the renin-angiotensin system (RAS) is already an old acquaintance, there are often exciting discoveries that improve our knowledge of it and open new therapeutic possibilities. Moreover, well-established drugs, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), or beta-blockers, show that their mechanism of action may be the result of parallel pathways other than the ones initially established. A detailed analysis of the RAS can be carried out in part through the study of the enzymes, named angiotensinases, involved in its cascade, whose activity is a reflection of the functionality of their peptide substrates. The study of these enzymes offers the possibility of controlling the effects of angiotensins through various pharmacological manipulations. For example, angiotensinase inhibitors or activators are being used or have been proposed as antihypertensive agents. They have also been suggested as analgesic and antidepressant drugs or targets for drug development against different pathologies such as Alzheimer's disease, epilepsy or ischemia. On the other hand, the analysis of brain asymmetry has revealed surprising results about the laterality of central and peripheral components of the RAS. Such studies indicate that the neurovisceral integration, already proposed by Claude Bernard (1867) should also be analyzed from a bilateral perspective. In this review, the RAS and the role of various angiotensinases implicated in the cascade are revisited. Therapeutic strategies involving some components of the RAS with an unusual vision resulting from a bilateral perspective added to their study are discussed.

Cardiovascular disease (CVD) is responsible for ∼27% of deaths worldwide, with 80% of these occuring in developing countries. Hypertension is one of the most important treatable factors in the prevention of CVD. Angiotensin-I converting enzyme (ACE) is a two-domain dipeptidylcarboxypeptidase that is a key regulator of blood pressure as a result of its critical role in the reninangiotensin- aldosterone and kallikrien-kinin systems. Consequently, ACE is an important drug target in the treatment of CVD. ACE is primarily known for its ability to cleave angiotensin-I to the vasoactive octapeptide angiotensin-II, but is also able to cleave a number of other substrates including the vasodilator bradykinin and N-acetyl-seryl-aspartyl-lysyl-proline (acetyl-SDKP), a physiological modulator of hematopoiesis. Numerous ACE inhibiors are available clinically, and these are generally effective in treating hypertension. However some adverse effects are associated with ACE inhibition, such as the persistent dry cough and the potentially fatal angioedema. The solution of ACE crystal structures over the last decade has facilitated rational drug design which has contributed to the development of domain-selective ACE inhibitors, the most notable of which include RXP407 (N-domain) and RXPA380 (C-domain), which in principle may herald new therapeutic approaches for ACE inhibition. Additionally, dual inhibitors to ACE and other targets such as neprilysin, endothelin converting enzyme and chymase have been developed. The success of ACE inhibitors has also led to the search for novel inhibitors in food and natural products and the structure guided screening of such libraries may well reveal a number of new ACE inhibitors.

In this study, physicochemical scale (P-scale), was recruited as a novel set of physicochemical descriptors derived from component analysis on four short of physicochemical properties variables (hydrophobic, electronic, steric and hydrogen bond contribution) of 20 coded amino acids, By using partial least squares (PLS), we applied P-scale for the study of quantitative structure activity relationship models (QASRs) on three angiotensin I converting enzyme (ACE) inhibitory peptides datasets (58 dipeptides, 55 tripeptides, and 50 tetrapeptides).The results of QSARs were superior to that of the earlier studies, with correlation coefficient (r(2)) and cross-validated(q(2)) equal to 0.902, 0.86; 0.985, 0.951 and 0.872, 0.77, respectively. By analysis, hydrophobic and steric properties of ACE-inhibitory peptide sequences play important roles in their bioactivities, and novel peptide sequence could be designed based on these properties of the amino acid residues. These results showed that P-scale descriptors can well represent the peptide sequence. Furthermore, the robust models show that P-scale descriptors can be further expanded for polypeptides and can serve as a useful quantitative tool for the rational drug design and discovery.

Recombinant antihypertensive peptide multimer (AHPM-2, 8kDa/68AA), a new designed polypeptide with potential antihypertensive effect in vivo, is composed of 15 low-molecular-weight antihypertensive peptides tandemly linked up according to the restriction sites of gastrointestinal proteases. After gene optimization, the DNA fragment encoding AHPM-2 was chemically synthesized, cloned into the pET32a, and successfully expressed in E.coli, above 90% in a soluble form. After chromatographic purification, the expressed fusion protein Trx-AHPM-2 was subject to the simulated gastrointestinal digestion, and the hydrolysate showed potent ACE inhibitory activity with an IC50 value of 4.5±0.3 μg ml-1. The active fragments from the AHPM-2 were identified by UPLC-MS/MS. This method will be useful in obtaining an appreciable quantity of recombinant AHP at low cost, and the intact AHPM-2 is expected to be developed into functional food for preventing hypertension as well as for therapeutic.

Diabetes mellitus is a common disease and contributes to a high degree of morbidity and mortality. Cardiovascular complications, including diabetic cardiomyopathy are major causes of morbidity and mortality in diabetic patients. Diabetic cardiomyopathy is a condition that affects the myocardium, primarily. It is not necessarily associated with ischemic heart disease, high blood pressure, valvular or congenital anomalies. The pathology of diabetic cardiomyopathy includes interstitial fibrosis, apoptosis of cardiomyocytes, abnormal energy utilization, small vessel disease and cardiac neuropathy. These pathologies are induced by hyperglycemia and oxidative stress. Biochemical as well as electrolyte changes, especially reduced calcium availability also occurs in the myocardium of diabetic patients. The abnormal structure and biochemistry of the myocardium result in functional problems such as diastolic and systolic dysfunctions, which may cause symptoms of dyspnea and inability to tolerate exercise. No single specific therapeutic agent can treat diabetic cardiomyopathy because once the disease is overt, the management may require a variety of approaches such as risk factors and lifestyle modification, glucose control (insulin, alpha glucosidase inhibitors, sulfonylureas, biguanides, meglitinides, thiazolidinediones and dipeptidyl peptidase 4 (DPP-4) inhibitors); hormones (IGF-1); ACE inhibitors (captopril, enalapril); angiotensin II receptor antagonists (losartan, olmesartan); beta adrenoreceptor antagonists (acebutolol, carvedilol); peptides (adrenomedullin); endothelin-1 receptor antagonists (bosentan, tezosentan); calcium channel blockers (amlodipine, verapamil); antioxidants (methalothionein, alpha tocopherol, alpha lipoic acid) and antihyperlipidemic drugs (simvastatin, fenofibrate, ezetimibe) to effectively treat patients with diabetic cardiomyopathy.

In recent decades, the most successful strategy for controlling blood pressure has been inhibition of the angiotensin-converting enzyme (ACE). ACE inhibitors of chemical synthesis (captopril, enalapril, ramipril and trandolapril) have been widely used clinically to reduce mortality in patients with heart failure, and in patients with recent myocardial infarction and heart failure or marked left ventricular dysfunction. In addition to preventive and therapeutic drugs, increased attention has been paid to identifying dietary compounds that may contribute to cardiovascular treatment and prevention. ACE inhibitory peptides, derived from a multitude of plant and animal proteins such as milk, soy or fish, represent sources of health-enhancing components. These ACE inhibitory peptides can be enzymatically released from precursor proteins in vitro and in vivo, respectively during food processing and gastrointestinal digestion. They have shown the ability to lower blood pressure by limiting the vasoconstrictory effects of Angiotensin II and potentiating the vasodilatory effects of Bradykinin. By using specific procedures they may be generated in or incorporated into functional foods for the development of 'natural' beneficial health products. Several products containing peptides with ACE inhibitory properties are currently on the market or in development. This review focuses on the use, application and future perspective of bioactive peptides with properties relevant to cardiovascular health.

Spectroscopic and structural elucidation of the peptides L-Valyl-L-Prolyl-L-Proline (1) and L-Isoleucyl-L-Prolyl-L-Proline (2) are reported on the basis of experimental linear-polarized IR-spectroscopy in solid-state, 1H-NMR data and DFT. Curiously, the experimental data shown that both peptides stabilized in solution and in solid-state neutral H2N-R-COOH form. Conformational analysis made, shown two strong intramolecular NH2-O=C-N(Amide) and O=C-OH-NH2 hydrogen bonds with lengths of 2.979 A and 2.475 A in (1) and 2.599 A and 2.507 A in (2) respectively. The presence of the Pro-Pro fold resulted to strong steric effect leading to the stabilization of free COOH and NH2 groups. The Erel values of zwitterion form are significant higher than the neutral forms with a difference of 1.2 and 0.9 kJ/mol. The manner of interaction of the peptides with angiotensin-I converting enzyme is proposed.

Silkworm pupae protein is a good source of high quality protein. The hydrolyzates of silkworm pupae protein catalyzed by neutrase, pepsin, acidic protease (Asperqiius usamii NO. 537), flavourzyme, alcalase, and trypsin with inhibitory activity on angiotensin I-converting enzyme (ACE) were identified by HPLC. The hydrolyzates catalyzed by acidic protease exerted the highest inhibitory activity on ACE. The hydrolyzing conditions were optimized by one-factor, factional factorial (FFD), and center composite (CCD) design methods, and response surface methodology (RSM). Statistical analyses showed that regression of the second-order model equation is suitable to describe ACE inhibitory bioactivity. The predicted inhibitory activity of hydrolyzates on ACE was 73.5 % at a concentration of 2.0 mg/ml. Optimized RSM technique decreased IC(50) of hydrolyzates inhibiting ACE to 1.4 mg/mL from 2.5 mg/ml. The molecular weight of the components of the hydrolyzates with inhibitory activity on ACE varied from less than 500 to about 1000 Da by ultra-filter analysis. These studies suggest that hydrolyzates of silkworm protein contain ACE inhibitory activity that could form a potential source of ACE inhibitor drugs.

Cardiovascular disease remains the leading cause of death worldwide. The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure, through the actions of angiotensin (Ang) II. Excessive RAAS activity may lead to hypertension and associated target organ damage. Indeed, RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT (1) blockers (ARBs) has proved to be successful treatment for arterial hypertension, heart failure and diabetes. Accumulating evidence suggests that arterial stiffness is an important and independent predictor of cardiovascular risk. More recently, a role for advanced glycation end-products (AGEs) in the development of arterial stiffening has been suggested. Advanced glycation end-products form by a nonenzymatic reaction between reducing sugars and biological proteins. Mechanisms underlying these alterations include AGE cross-linking of collagen and AGE interactions with circulating proteins and AGE receptors. New pharmacologic agents that prevent AGE formation, break cross-links, or block AGE receptors reduce vascular and myocardial stiffness, inhibit atherosclerotic plaque formation, and improve endothelial function. These agents promise to reduce the risk of isolated systolic hypertension, diastolic dysfunction, diabetes and thus, heart failure.

Angiotensin II (AngII) is the major regulator of blood pressure, electrolyte balance, and some endocrine functions related to cardiovascular diseases. Moreover, it has been shown that AngII plays a role in various pathological situations involving tissue remodelling and in cancer. Two distinct subtypes of AngII receptors [type 1 (AT1) and type 2 (AT2)] have been identified, and both belong to the G protein-coupled receptor (GPCR) superfamily. A knowledge of the 3D structure of AT receptors could be of great help in the task of understanding molecular interactions, and in the rational design of specific ligands; however, as GPCRs are membrane-bound proteins, high-resolution structural characterization is still an extremely difficult task. For this reason, great importance has been placed on molecular modelling studies and in particular, on homology modelling (HM) techniques. In this review, we report and analyze the main experimental data and the computational procedures and validation methods used for the construction of the AT receptors, describing in details the most successful results and new trends.

Food proteins contain latent biofunctional peptide sequences within their primary structures which may have the ability to exert a physiological response in vivo. A large range of biofunctional peptides have been isolated from food proteins including opioid, immunomodulatory, antimicrobial, mineral binding, growth and muscle stimulating, anti-cancer, proteinase and angiotensin converting enzyme (ACE, EC 3.4.15.1) inhibitory peptides. The biofunctional peptide activity currently most studied in food proteins appears to be those that inhibit ACE. ACE plays a central role in the regulation of blood pressure (BP) through the production of the potent vasoconstrictor, angiotensin (Ang) II , and the degradation of the vasodilator, bradykinin (BK). ACE inhibitory peptides may therefore have the ability to lower BP in vivo by limiting the vasoconstrictory effects of Ang II and by potentiating the vasodilatory effects of BK. These ACE inhibitory peptides can be enzymatically released from intact proteins in vitro and in vivo during food processing and gastrointestinal digestion, respectively. ACE inhibitory peptides may be generated in or incorporated into functional foods in the development of 'natural' beneficial health products. Several products are currently on the market or are in development that contain peptide sequences which have ACE inhibitory properties. Detailed human studies are required in order to demonstrate the efficacy of these bioactive peptides prior to their widespread utilisation as physiologically beneficial functional foods/food ingredients.

A correct representation of intermolecular interaction energies is necessary for reliable drug-receptor docking studies. While ab initio quantum chemistry with extended basis sets is the most accurate tool for that purpose, its use is precluded for very large molecular complexes. This constitutes the incentive for the development of accurate molecular mechanics potentials, in which the first-order electrostatic, and the second-order polarization energy contributions, are of essential importance. In this paper, we review the most important steps in the development of anisotropic, polarizable molecular mechanics (APMM) procedures. Among these, we illustrate validation tests of the ab initio-grounded, polarizable molecular mechanics potential, SIBFA (Sum of Interactions Between Fragments Ab initio computed). These are done by comparisons with parallel quantum-chemical (QC) results on representative multiply hydrogen-bonded complexes and polycoordinated complexes of one, or of two, divalent metal cations. For both kinds of complexes, the need to reproduce the non-additivity of the QC interaction energies is emphasized. One difficulty arises upon handling flexible molecules, due to the need to account simultaneously and consistently for the onset of inter- and intra-molecular polarization and charge-transfer effects. A new approach in the context of SIBFA was recently developed towards this aim, and tested in two cases of conformation-dependent cation-ligand interaction energies. The first relates to the complexes formed between the mecapto-carboxamide anion, an essential building-block of several Zn-metalloenzyme inhibitors, and Zn(II). The second relates to the complexes of the tetra-anionic pyrophosphate anion, a key building-block of ATP and GTP, with one or two divalent Zn(II) cations used as a probe. In the domain of applications, two recent studies are then presented. The first is the docking of the captopril drug to the active site of the binuclear Zn(II)- beta-lactamase enzyme. The second is the complex of a non-hydrolyzable analog of ATP with the active site of a binuclear Mg(II)-dependent kinase. An extension to an open-shell cation, Cu(II), is finally presented. The encouraging results presented in this review show that APMM procedures could be used in large-scale studies of ligand and drug-receptor interactions.

Genomic epidemiologic data, increasingly supported by clinical outcomes results, strongly suggest that overactivity of angiotensin I-converting enzyme (ACE) may underlie most age-related diseases. Angiotensin II, the main product of ACE, is a pleiotropic hormone, capable of serving as a neurotransmitter, growth factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. So it is perhaps not surprising that the ACE D/D genotype is associated with several major psychiatric diseases, most cancers except prostate cancer (where the D/D genotype is actually protective), most cardiovascular diseases, most autoimmune diseases, and even infectious diseases like tuberculosis and HIV. In a preliminary study, angiotensin II blockade appeared to hasten recovery from West Nile virus encephalitis; it may be equally useful in SARS. The ACE gene underwent duplication at the origin of Chordata, just before the "Cambrian Explosion" in the number of species. The ancestral, unduplicated form of ACE is still expressed during the terminal differentiation of human spermatocytes, suggesting a critical role in reproduction. The crystal structure of testicular ACE (tACE) was recently published. Computer modeling suggests that tACE may be activated by both mechanical forces and reducing agents. The duplicated form of ACE (somatic ACE, sACE) is expressed in areas of high fluid flow. sACE may auto-dimerize via a novel protein motif, the "disulfide zipper." The sACE dimer is predicted to have higher catalytic efficiency and redox resistance than tACE.

Angiotensin-I Converting Enzyme (ACE) is a Zinc Metallopeptidase of which the three-dimensional structure was unknown until recently, when the X-ray structure of testis isoform (C-terminal domain of somatic) was determined. ACE plays an important role in the regulation of blood pressure due to its action in the frame of the Renin-Angiotensin System. Efforts for the specific inhibition of the catalytic function of this enzyme have been made on the basis of the X-ray structures of other enzymes with analogous efficacy in the hydrolytic cleavage of peptide substrate terminal fragments. Angiotensin-I Converting Enzyme bears the sequence and topology characteristics of the well-known gluzincins, a sub-family of zincins metallopeptidases and these similarities are exploited in order to reveal common structural elements among these enzymes. 3D homology models are also built using the X-ray structure of Thermolysin as template and peptide models that represent the amino acid sequence of the ACE's two catalytic, zinc-containing sites are designed and synthesized. Conformational analysis of the zinc-free and zinc-bound peptides through high resolution 1H NMR Spectroscopy provides new insights into the solution structure of ACE catalytic centers. Structural properties of these peptides could provide valuable information towards the design and preparation of new potent ACE inhibitors.

Hypertension remains one of the most unmet medical needs of this century. While many drugs are available for treating hypertension, efforts are still insufficient to find potent therapeutic agents since cause for hypertension in all patients is not the same. Angiotensin-converting enzyme inhibitors (ACEIs) have emerged as an important class of drugs in the treatment of hypertension, congestive heart failure (CHF), protenuric renal disease, myocardial infarction and stroke. This class of drugs blocks the conversion of angiotensin I to angiotensin II and prevents bradykinin breakdown. However, the lack of specificity of ACEIs leads to the frequent side effects like cough and angio-oedema. Recently developed, specific non-peptide and orally active angiotensin receptor blockers (ARBs) have become the prime therapeutics as they alone or co-administration with ACE inhibitors can control the renin angiotensin disorders. This review explores recent developments in the design, synthesis, and structural modifications of ACE inhibitors as well as angiotensin receptor blockers.

A review of the Electron-Conformational (EC) method of pharmacophore (Pha) identification and quantitative bioactivity prediction in drug design and toxicology is presented, which includes the latest advances and improvements of the method as a whole and details of its realization with illustration of results. In the first part devoted to Pha identification the data of conformational analysis and electronic structure calculation of each of the molecules in the training set are used to construct EC matrices of congruity (ECMC) that include atomic interaction indices as diagonal elements, and bond orders and interatomic distances as off-diagonal elements. Multiple comparisons of the ECMC's of the active compounds between themselves and with those of inactive compounds allows one to separate a relatively small number of matrix elements that within certain tolerances are common to all the ECMC's of the active compounds, while not present in the same combination in the inactive compounds. This is the EC submatrix of activity that represent the Pha, while the tolerances characterize the Pha flexibilities. Distinguished from QSAR approaches, the Pha is obtained here by computational (non-statistical) methods only. The second part of the problem, quantitative activity prediction, is based on using the Pha flexibilities together with the anti-Pha shielding and other auxiliary groups influence in a parameterization and regression analysis procedure that allows for quantitative prediction. An original approach is suggested that side steps the multi-conformational implications. This post-Pha problem is similar to a QSAR approach with special physically transparent descriptors that allow one to avoid chance correlations in the regression procedure. Illustration of the method is given for several drug design problems in which, where sufficiently accurate experimental data are available, the identification of the Pha as a necessary condition of activity is almost 100% correct, while quantitative activity prediction is near to the accuracy of the experimental data, 80% - 90%.

This paper reviews bioactive peptides, biogenic peptides, opioid peptides, immunostimulating peptides, mineral soluble peptides, antihypertensive peptides and antimicrobial peptides originating from food materials and enzymatic hydrolysis of proteins. Antihypertensive peptides are extensively reviewed and have been divided into angiotensin I-converting enzyme inhibitory peptides and others. These peptides are produced in the enzymatic hydrolysate of treated food materials such as milk, animal and fish meat, maize, wheat, soybeans and egg, and also from microbe-fermented products. Peptides with strong antihypertensive effects on spontaneously hypertensive rats are discussed and are divided into high and low angiotensin I-converting enzyme inhibitory activities. In addition, new topics from our studies on antihypertensive peptides are introduced. Efficacies of these peptides in clinical studies and differences with medicinal substances are summarized. Recent studies in this area shown the possibility of using biogenic peptides for improvements in treatment or prevention of hypertension.

Design and synthesis of metabolically stable peptide analogs that can either mimic or block the bioactivity of natural peptides or enzymes is an important constituent of bioorganic and medicinal chemistry research. Isosteric replacement of a scissile peptide bond represents a viable and popular approach in the rational design of peptidomimetics. Peptidomimetics find applications as drugs, in protein engineering and so on. This is evident from the wealth of therapeutically useful peptidomimetic leads incorporating any of the peptide isosteres that are currently available. In this review, we have given a brief account of the types of peptide isosteres widely known till date. With this background, we have described some of the recent developments in synthetic approaches. This includes methods involving a common intermediate to synthesize different possible isosteres and their peptide analogs, solid phase synthesis and combinatorial approach. One such method involving stereoselective nitrile oxide cycloaddition as the key step has been studied extensively in our research laboratory. Finally, we have also discussed about some of the recent reports on the design and inhibitory activities of peptidic or non-peptidic analogs against aspartic proteases (HIV-1, renin, ACE and pepsin) and peptide analogs of an immunomodulating hexapeptide.

A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A(4) hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.

Angiotensin II, the primary active hormone in the Renin-Angiotensin System is a major vasoconstrictor implicated in the cause of hypertension. Research efforts have focused in the treatment of disease by blocking its release and more recently by competing its action on AT(1) receptors. This approach generated in the pharmaceutical market, losartan, and other derivatives. To better understand the stereoelectronic requirements that lead to the molecular basis of hypertension the stereochemical features of angiotensin II and its antagonists are studied.