Carla S. S. Teixeiraa,
Rita Biltesa,
Caterina Villaa,
Sérgio F. Sousabc,
Joana Costaa,
Isabel M. P. L. V. O. Ferreiraa and
Isabel Mafra*a
aREQUIMTE-LAQV, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal. E-mail: isabel.mafra@ff.up.pt
bAssociate Laboratory i4HB – Institute for Health and Bioeconomy, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
cUCIBIO – Applied Molecular Biosciences Unit, BioSIM – Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
First published on 1st December 2023
Edible insects have been proposed as an environmentally and economically sustainable source of protein, and are considered as an alternative food, especially to meat. The migratory locust, Locusta migratoria, is an edible species authorised by the European Union as a novel food. In addition to their nutritional value, edible insects are also sources of bioactive compounds. This study used an in silico approach to simulate the gastrointestinal digestion of selected L. migratoria proteins and posteriorly identify peptides capable of selectively inhibiting the N-subunit of the somatic angiotensin-I converting enzyme (sACE). The application of the molecular docking protocol enabled the identification of three peptides, namely TCDSL, IDCSR and EAEEGQF, which were predicted to act as potential selective inhibitors of the sACE N-domain and, therefore, possess bioactivity against cardiac and pulmonary fibrosis.
The migratory locust, Locusta migratoria (order Orthoptera, family Acrididae) is a very unpopular species around the world due to its ability to cause extensive damage to crops. However, the dry adult insect has a rich nutritional composition (50.4 ± 2.0% crude protein, 19.6 ± 0.8% crude fat, 4.8 ± 0.7% carbohydrates, 15.6 ± 1.7% crude fibre, 6.2 ± 0.5% ash and 3.8 ± 0.2% moisture), providing 490.4 ± 4.0 calories per 100 g of the dry product8 and is consumed as a food delicacy in several regions of the world for centuries.9 In the European Union, it was classified as a novel food according to Regulation (EU) 2015/2283 on novel foods10 and recently considered safe for human consumption.11 The European Union legislation allows it to be placed on the EU market as frozen adult insects without legs and wings, dried without legs and wings and ground with legs and wings.11
Besides the nutritional value of insects, the exploitation of nutraceutical properties can be a stimulus for increased interest in their intake in Western diets. In a particular case of migratory locust, Ochiai et al. demonstrated that the dietary administration of insect powder to rats improved fat metabolism and promoted therapeutic/ameliorating effects against dyslipidemia.12
Most studies concerning the bioactive properties of edible insects focused on the identification of peptides with antihypertensive, antidiabetic and antioxidant properties.13 In a previous work, we reported that insects can also be a source of bioactive peptides with antifibrosis properties. An in silico protocol that simulated gastrointestinal (GI) digestion of the house cricket (Acheta domesticus) identified several peptides capable of selectively inhibiting the N-subunit of the somatic angiotensin-I converting enzyme (sACE; EC 3.4.15.1).14 To our knowledge, that was the first study associating the consumption of insects with potential antifibrosis effects.14
The sACE is a 150–180 kDa dipeptidyl carboxypeptidase that also displays endopeptidase activity and can be found in epithelial, endothelial and neuroepithelial cells.15 It is a promiscuous enzyme that has several substrates (e.g., angiotensin I (Ang I), N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), substance P, enkephalins, gonadotropin-releasing hormone (GnRH), N-formylmethionine-leucyl-phenylalanine luteinizing hormone-releasing hormone (LHRH), neurotensin, kinins and amyloid-beta), being implicated in several physiological processes, including blood pressure control, fibrosis, erythropoiesis, haematopoiesis, myelopoiesis immunomodulation, renal development and function, cell signalling or amyloid-beta clearance.16
sACE is composed of two homologous catalytic domains, known as the N- and C-domains, each harbouring a catalytic zinc ion at the active site. Overall, the two domains share 65% sequence homology with each other,17 though for their catalytic pocket residues, the homology can reach 89%. The detailed analysis of their active sites showed that although most key residues involved in inhibitor-binding are common among both active sites, there are some domain specific structural differences that are responsible for their different kinetic profiles.18 The C-domain is primarily responsible for catalysing the last step in the production of the mitogenic and hypertensive octapeptide, angiotensin II (Ang II), through the cleavage of the His-Leu dipeptide from the C-terminus of angiotensin I (Ang I). Both C and N domains inactivate the vasodilator nonapeptide bradykinin (BK) with the same efficiency through sequential cleavage of Phe-Arg and Ser-Pro dipeptides.19 Since C-domain inhibition is an effective way to reduce blood pressure, sACE inhibitors are extensively used for the treatment of hypertension and cardiovascular disease. The current problem is that most of the available sACE inhibitors are not domain-specific, resulting in elevated levels of bradykinin that can trigger side effects, such as cough and angioedema.20
The N-domain is exclusively responsible for the hydrolysis of the tetrapeptide Ac-SDKP (N-acetyl-Ser–Asp–Lys–Pro). AcSDKP is a natural inhibitor of hematopoietic stem cell proliferation21 and also prevents the proliferation of fibroblasts in the myocardium, aorta and kidneys, leading to the reduction of collagen deposition in hematopoietic stem cells of cardiac and pulmonary tissues.15,22,23 Since excess collagen deposition in these tissues has been identified as a mechanism for the pathogenesis of fibrosis, the selective inhibition of the N-domain of sACE has been proposed as a possible treatment for cardiac and pulmonary fibrosis, without interfering with the C-domain function in blood pressure and water and salt homeostasis.18
The aim of this work is to apply a molecular docking protocol to identify peptides originating from the simulated GI digestion of L. Migratoria proteins, capable of selectively inhibiting the N domain sACE and, therefore, with potential antifibrosis effects.
To raise the probability of obtaining new peptides, characteristic and/or specific L. migratoria species with unknown bioactivity, the protein selection criterion was the lowest percentage of sequence identity (percentage of residues identical between two proteins divided by the length of the shortest sequence)27 compared to proteins from other non-target species when a protein BLAST was performed on NCBI. However, since the proteome of L. migratoria is not complete, a certain degree of sequence identity was accepted for this analysis, depending on the available sequences and the database from where they were collected.
Additionally, the peptides selected for the last steps were also submitted to the Food-derived bioactive peptides (DFBP)29 database (https://www.cqudfbp.net/) and a literature check was performed to confirm that they do not have any previously identified biological activity.
When preparing the structures for protein–ligand docking, water molecules and additional ligands were removed. The ligands Ang-II and BJ2 were saved for later use to optimise the docking protocol for each target. This was accomplished through redocking and comparing the predicted poses with the experimental ones by root mean square deviation (RMSD). Preparation of the structure of the targets and addition of the hydrogen atoms was done using the GOLD software31 according to the recommended protocol, as in previous studies involving other proteins.32–35
Docking was performed using GOLD software using the PLP scoring function.38 The co-crystallised ligands, BJ2 and Ang-II were used as the reference to evaluate and optimise the accuracy of the docking protocol for each target. The conformation of each ligand was randomised, and the ligands were redocked against their initial target. Different settings were considered to ensure an accurate reproduction of the pose of the reference ligands. The optimised parameters included the position of the centre and radius of the docking region, and a number of independent genetic algorithm (GA) runs.
The final optimised protocol for each target was applied to dock all 245 peptides against each target structure. The most stable predicted conformations for each peptide were recorded and analysed. The PLP binding score for each peptide to each target protein was also registered and compared with the binding scores of the reference molecules Ang-II and BJ2. The GOLD's PLP scoring values are non-dimensional, with higher values indicating a stronger association.
As the main objective of this study was to target new and highly specific peptides of L. migratoria, a selection criterion of sequence identity below 81% was used to analyse the 93 identified proteins, reviewed by Swiss-Prot, available at the UniProtKB database. Similarly, for the 3598 protein sequences available in NCBI database, a criterion of less than 55% sequence identity was established for protein selection. As the number of proteins obtained from the two databases was significantly different, the selection criteria were adapted to each one to restrict the number of proteins selected for the next steps.
The adopted procedure resulted in a total of 9 protein sequences, 3 obtained from UniProtKB database and 6 obtained from the NCBI protein database. Their NCBI/UniProtKB accession numbers and relevant features are described in Table 1.
Database | Accession number | Protein name | Length | Sequence | Species with higher sequence identity | Percentage of sequence identity | Number of fragments obtained after simulated GI digestion | Number of peptides (>1aa) with known biological activity | Number of peptides (>1aa) with unknown biological activity |
---|---|---|---|---|---|---|---|---|---|
NA – no sequence identity found. | |||||||||
NCBI | ALD51386.1 | Odorant receptor 126 | 428 | MEFESMMGPGLPLMRLTGLWQMGRQGGGVSRGLRLATIVLSVLLVVAGSTLHLVFDTPDQFEDITLCGFNIDIVSLDLLKGVLFVVQGAPLRELVQLLCDARAGFTFADINHAIRGRYEAVADRMRILLQATVVLPLVGWLSAPLMSRLAAGAGGSRAPRQLPVPAWLPVDIHATPTYELLYALQAFGCTAAGAFSICVDAFFIRLMLLISAEIEVLCENISAIGVPHPAQGSGGCICRCQPNAADLACTCKGCVKAFTSSPEEASDEMYQLLVKAVRHHQTIIRMVALLQQTMDALVFIVLFANMANLCCSLFATAILLQRGGSLTKTLKGLSAVPVVLYQTSLYCLFGHIVTDQSEKLYNAAISCGWVNCDARFKRSLLIFMVEAMKPLEITVGKFCKLSRQMLLQVFHSSYALMNLLYYYHYNTE | Ceracris kiangsu | 55% | 167 | 21 | 62 |
AKN21235.1 | Cchamide-2 precursor | 133 | MSAKQHTAVALLGDAAPSAVHAARRIRRRPVRRAADRGGVPVRAAPSAGHAARRRRQTWVHGVRALVLRRPRQARRPGAGGGGAGRGGGGSGGAAGRPGGAGGGGGAGGGGTAIPPVAVPAAVAAACLPATVS | NA | NA | 34 | 7 | 14 | |
AMO66175.1 | Defensin 4 | 69 | MKNSTVFFLVGLLTTAGIAFCSAAPAQSVQDDRQAHLTCDSLSALGVPCAAVRCVKGAYCQHGVCHCRV | Schistocerca cancellata | 52% | 21 | 1 | 12 | |
API80737.1 | Autophagy-related protein 2 | 220 | MRGMSLLLLSNEHSFPCIAEIVSTVRIEILLTHSYFNSLSNNRKPGIKLLFHQKLYFMFVSEAMFSNCRFLQLSVFNMLLVFNTAIRNSMNGLTYVIDIINPETETVLYSAVHLLYILRRTEDWSHTLSTQDSSCFAGYMVQKGRNTIGDSSSECSIFSDFPFLEMLPLHHMNHRHFFRRKVVNFRLQLVLTRNSSRSVYQCVQNGSLLRCMMETLCIEI | NA | NA | 109 | 22 | 24 | |
AQY60265.1 | CYP3117C1 | 499 | MSVWLVFGAALATVCACALAVASWLWATRLQTAAPGPPTWPLLGNVQHFLKQPVLLEHAADLYKQYGDVFRFYVGPKLVVVVTKPEDVKRVLVTTKWQERDPYFLGTLRKVTGNGLLINSGEVWQRHRKALEPTFHYTALHRYLDTFNKEVCLLSERLAAMGGQESDVLPLMCLSSLRITMCALGGMEYDVVEPDQYQQQQLASEFIGFLKVFQATMFRPWKAINSLMWMSEDGRKLKKIIGMAKDVTNRYLAALRVYNTKLEITSHFSSLLLEEKPEMQEMDDKISDEVVTVAVTATETMAGALAYALSALGLYPEWQVKAQQQLDEVFGEGGDFLRPATLEDIGKLTVIDAIVKETLRLFTVVPFLPRIIDEDIPLAGGRYVAPRGCCVAVASFLTHRDPDLYPEPDKFDPGRFLPGGSATSRKPFSYIPFGAGSRVCLGSSFATLEMKVTLATLLRQFTVVSGSTRKDLEHTLFSITAHPLKGFRLSFRARKEQSL | Schistocerca cancellata | 55% | 197 | 23 | 81 | |
DAA64589.1 | Serine protease-like protein 1 | 276 | MIKEAVLVLALAACVSAAVLPVRRIAHSGPLRKTGLKQGRIVGGKEAEEGQFPYSVSIQWQLSGVSSHFCGGALVKDDVVVTAGQCAHVVTYGLTTVVAGRVYMDESVYGQSTLWEISHPEYKVVNNHAINDIAVFTLTVGFDLSDKINVIGLPSQDQKPYAQAATLSGWGSTSNSMLPETSDTLHYAEVTVIPTVNCYALMTDDSTFNNNNICSGPVTGKISSCVGDIGSPLVQYGNLIGVVSWNTVPCGTFGMPIVYTRVSAYSDWIKEYMDTK | Schistocerca nitens | 51% | 83 | 13 | 45 | |
Uniprot | P14570 | ATP synthase protein 8 | 52 | MPQMSPMMWFSLFIMFSMTMMLFNQLNFFSYKPNKIMSSNNKIKKKNINWMW | Oedaleus asiaticus | 80.77% | 36 | 8 | 4 |
P19872 | Adipokinetic prohormone type 3 | 77 | MQVRAVLVLAVVALVAVATSRAQLNFTPWWGKRALGAPAAGDCVSASPQALLSILNAAQAEVQKLIDCSRFTSEANS | Schistocerca gregaria | 71.43% | 24 | 5 | 9 | |
P80059 | Pars intercerebralis major peptide D1 | 54 | SCTEKTCPGTETCCTTPQGEEGCCPYKEGVCCLDGIHCCPSGTVCDEDHRRCIQ | Schistocerca cancellata | 71.15% | 9 | 0 | 6 |
To assess the differences in the affinities between the two sACE domains, two crystallographic structures were used:
(1) the N-domain complexed with BJ2 (PDB ID: 6EN5), a potent inhibitor that is 84-fold more selective towards the N-domain than towards the C-domain (Fig. 1a);
Fig. 1 Pymol representation of the crystallographic structures (represented in the cartoon) of (a) N-domain of sACE complexed with BJ2 (PDB ID: 6EN5) and (b) C-domain of sACE complexed with Ang-II (PDB ID: 4APH). Pymol representation of the superimposition of the binding poses of the reference inhibitors BJ2 and Ang-II in the complex crystallographic structure (represented in licorice and coloured in magenta) and after the re-docking protocol (represented in licorice and coloured in green) in (c) the N-domain of sACE and (d) the C-domain of sACE. Zn2+ is represented in grey. |
(2) the C-domain complexed with the reaction product and competitive inhibitor Ang-II (PDB ID: 4APH) (Fig. 1b).
To validate the docking algorithm, the co-crystallised inhibitors (reference inhibitors Ref1 (BJ2) and Ref2 (Ang-II)) were removed from the crystallographic structure of the protein, randomised and re-docked into their active site. The crystallographic and re-docked poses were superimposed and represented in Fig. 1c and d.
For the N-domain both inhibitor structures are well aligned inside the enzyme's active site (Fig. 1c), suggesting that the adopted molecular docking protocol can reproduce the crystallographic pose very well and, therefore, it can be applied to predict the binding poses of the studied peptides. For the C-domain, the docking algorithm was not so effective in reproducing the crystallographic pose (Fig. 1d). This result was not surprising since the crystallographic structure was reported to present some difficulties in defining the exact coordinates for all residues of the ligand, Ang-II, suggesting that it was able to bind to the C-domain active site in two different ‘sliding’ conformations.30 The docking scores obtained for the 241 peptides and the reference inhibitors (Ref1 and Ref2) against the two targets (PDB ID: 4APH and 6EN5) are reported in Table S2 of the ESI.†
Since the aim of this work is to identify peptides that are potential selective inhibitors of the N-domain of sACE, three selection criteria (SC1–3) were defined and sequentially applied to the docking scores obtained for the 6EN5 structure.
(SC1) Peptides with docking score (ds) values higher than that obtained for the reference inhibitor (Ref1, ds = 119.68) means that the peptides may have a higher affinity for the active site than the crystallographic inhibitor.
(SC2) Peptides in which the difference between the docking scores for the N- and C-domains (ds N-domain minus ds C-domain) is higher than 20 indicates that the peptides have higher affinity for the N-domain than for the C-domain.
(SC3) Peptides with a ratio between the docking score and the number of non-H atoms higher than 2 eliminate the peptides whose docking score was positively influenced by the size of the peptide avoiding the bias of the result.
After applying the first criterion (SC1), 49 peptides were selected. The application of the second criterion (SC2) restricted the selection to 15 peptides which were reduced to 14 after removing peptide #118 which did not comply with the third criterion (SC3) (Table 2). Therefore, a total of 14 peptides with potential selectivity for the N-domain of sACE were obtained and followed for further analysis. The absence of known biological activities associated with the selected peptides was confirmed using the DFBP database.
SC1 | SC2 | SC3 | ||||||
---|---|---|---|---|---|---|---|---|
Peptide ID | Peptide code | ds 6EN5 (>119.68) | ds 4APH | ds 6EN5–ds 4APH (>20) | Non-H atoms | ds/non-H atoms (>2) | Potential IgE binding | Potential cross-reactivity |
#17 | VIDIIN | 129.46 | 90.24 | 39.22 | 48 | 2.70 | No | Per a 1, Periplaneta americana |
#31 | TTAGIAF | 123.93 | 103.49 | 20.44 | 48 | 2.58 | No | No |
#40 | TCDSL | 127.47 | 94.89 | 32.58 | 36 | 3.54 | Yes | No |
#45 | SVSIQW | 131.06 | 102.03 | 29.03 | 51 | 2.57 | No | No |
#77 | QTIIR | 135.05 | 98.24 | 36.81 | 44 | 3.07 | No | Sar s 1, Sarcoptes scabiei |
#81 | QQQQL | 122.3 | 97.04 | 25.26 | 45 | 2.72 | Yes | Allergenic protein, Oryza sativa |
#85 | QGGGVSR | 130.16 | 108.32 | 21.84 | 46 | 2.83 | No | Asp f 9, Aspergillus fumigatus |
#107 | PEPDK | 122.26 | 96.28 | 25.98 | 41 | 2.98 | Yes | No |
#109 | PEDVK | 121.45 | 97.46 | 23.99 | 41 | 2.96 | No | No |
#130 | IDCSR | 129.11 | 102.2 | 26.91 | 40 | 3.23 | Yes | No |
#145 | GGQESDVL | 133.44 | 113.31 | 20.13 | 56 | 2.38 | No | Asp FII, Aspergillus fumigatus |
#164 | EITVGK | 129.72 | 104.97 | 24.75 | 45 | 2.88 | No | No |
#173 | EAEEGQF | 138.65 | 116.28 | 22.37 | 57 | 2.43 | No | No |
#186 | DESVY | 130.1 | 103.07 | 27.03 | 43 | 3.03 | Yes | No |
Most of the identified interactions are established between the peptides and residues that are conserved among both active sites. Some of those conserved N-domain/C-domain residues are: Gln259/281, Lys489/511, Tyr498/520, His331/353, His491/513, Tyr501/523, Ala334/356,18 His361/383, His365/387, Phe435/457, Phe505/52740 and Asp336/358.41
According to the literature, the molecular basis beyond the selectivity of the N- and C-domains relies on the replacement of some residues of the binding pocket with others possessing different chemical properties.18 The literature refers to five main N-domain/C-domain substitutions, namely the replacement of a positively charged arginine (Arg381) in the N-domain with a negatively charged glutamate (Glu403) in the C-domain and the replacement of four hydrophilic residues in the N-domain (Tyr369, Ser357, Thr358 and Thr496) with four hydrophobic residues in the C-domain (Phe391, Val379, Val380, Val518). These substitutions affect the sACE binding site moieties influencing the type of interactions established between the ligands and the active site. The aforementioned residues have already been used as part of a successful targeting approach towards the design of the N-domain selective inhibitor BJ2, which was co-crystallised with the sACE structure selected for the present docking studies.18 Considering that the BJ2 inhibitor showed potent inhibition and was 84-fold more selective toward the N-domain, the potential selectivity of the 14 peptides selected in this work was determined by evaluating their capability to establish intermolecular interactions with the Arg381, Tyr369, Ser357, Thr358 and Thr496 residues of the N-domain active site. To discard the possibility of the interaction of peptides with the corresponding C-domain residues, their capability to bind to residues Glu403, Phe391, Val379, Val380, and Val518 of the C-domain was also evaluated. The result of the analysis of the intermolecular interactions between the domain specific residues and the selected peptides are presented in Table 3, which shows that:
(1) all peptides establish at least one interaction with one of the four N-domain specific residues Arg381, Tyr369, Thr358 and Thr496;
(2) for 12 (#17, #31, #40, #77, #81, #85, #107, #109, #130, #164, #173 and #186) out of the 14 peptides, the redocked (Ref1) and crystallographic BJ2 poses establish a hydrogen bond with Tyr369;
(3) peptide #145, excluded from point (2) establishes a hydrophobic interaction with Tyr369;
(4) 5 peptides only interact with N-domain specific residues and not with any C-domain specific residues (#40, #45, #130, #145, and #173).
Enzyme target | Type of interaction | Peptide ID | 17 | 31 | 40 | 45 | 77 | 81 | 85 | 107 | 109 | 130 | 145 | 164 | 173 | 186 | Ref1 (BJ2) | Ref2 (Ang ii) | Crystallographic pose | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Residue | ||||||||||||||||||||
x, molecular interaction between the peptide and enzyme residue. −, no molecular interaction. | ||||||||||||||||||||
N-domain | Hydrogen bonds | 358 | THR | − | − | − | x | − | − | − | − | − | − | − | − | x | − | − | − | − |
369 | TYR | x | x | x | − | x | x | x | x | x | x | − | x | x | x | x | − | x | ||
496 | THR | x | − | x | − | − | x | − | − | x | − | x | x | x | − | − | − | − | ||
Hydrophobic interactions | 358 | THR | x | − | − | − | x | x | − | − | − | − | x | − | − | − | − | x | − | |
369 | TYR | − | − | − | − | − | − | − | − | − | − | x | − | − | − | − | − | − | ||
381 | ARG | − | − | − | − | − | − | − | − | − | − | x | − | x | − | − | − | − | ||
496 | THR | x | − | − | x | x | − | − | − | − | − | − | x | − | − | − | − | x | ||
C-domain | Hydrogen bonds | 403 | GLU | − | − | − | − | − | − | − | − | x | − | − | − | − | − | − | − | − |
Hydrophobic interactions | 391 | PHE | x | x | − | − | x | − | − | x | x | − | − | − | − | − | − | − | x | |
403 | GLU | − | − | − | − | − | − | x | − | − | − | − | − | − | − | − | x | − | ||
518 | VAL | − | − | − | − | − | x | − | x | − | − | − | x | − | x | − | x | x | ||
Salt bridges | 403 | GLU | − | − | − | − | x | − | − | − | − | − | − | − | − | − | − | − | − |
There are several conditions for the last group of 5 peptides to be considered as potential N-domain selective inhibitors: they establish a hydrogen bond or/and a hydrophobic interaction with at least one specific residue of the active site of the N-domain and they do not interact with any specific residue of the active site of the C-domain (Fig. 2). Considering that the hydrogen bond with Tyr369 may positively influence the selectivity of the molecule, this final selection may be restricted to 3 peptides: TCDSL (#40), IDCSR (#130) and EAEEGQF (#173).
This was the first study that reported the potential bioactivity of these 3 peptides and the second that demonstrated that GI digestion of edible insect proteins can produce peptides with antifibrosis bioactivity. Information in the literature on specific inhibitors of the N-domain of sACE is still very scarce and, although requiring in vitro/in vivo validation, these results are a valuable contribution to the rational design of specific inhibitors of the sACE N- and C-domains. It also demonstrates that including insects in diets can bring unexplored health benefits.
The selection criteria applied allowed us to filter the initial pool of peptides and propose a group of 14 peptides for an in-depth evaluation. After a careful assessment of the intermolecular interactions between each peptide, the reference inhibitor and the residues lining the active sites of the two sACE domains, a group of 14 peptides was restricted to 3 peptides: TCDSL (#40), IDCSR (#130) and EAEEGQF (#173). The allergenicity prediction tools suggested that although peptides #40 and #130 could have the potential to induce IgE-binding in sensitised individuals, apparently none of the three peptides leads to IgE cross-reactivity in patients with pre-existent allergies. However, these results should be confirmed experimentally.
In conclusion, peptides TCDSL (#40), IDCSR (#130) and EAEEGQF (#173) are potential selective inhibitors of the sACE N-domain and their bioactivity against fibrosis should be evaluated through in vitro and in vivo studies.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3fo04246d |
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