Isolation and Characterization of NpCI, a New Metallocarboxypeptidase Inhibitor from the Marine Snail INerita peloronta/I with Anti-IPlasmodium falciparum/I Activity
Metallocarboxypeptidases are zinc-dependent peptide-hydrolysing enzymes involved in several important physiological and pathological processes. They have been a target of growing interest in the search for natural or synthetic compound binders with biomedical and drug discovery purposes, i.e., with...
Gespeichert in:
Veröffentlicht in: | Marine drugs 2023-01, Vol.21 (2) |
---|---|
Hauptverfasser: | , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | |
---|---|
container_issue | 2 |
container_start_page | |
container_title | Marine drugs |
container_volume | 21 |
creator | Cabrera-Muñoz, Aymara Sierra-Gómez, Yusvel Covaleda-Cortés, Giovanni Reytor, Mey L González-González, Yamile Bautista, José M Avilés, Francesc Xavier Alonso-del-Rivero, Maday |
description | Metallocarboxypeptidases are zinc-dependent peptide-hydrolysing enzymes involved in several important physiological and pathological processes. They have been a target of growing interest in the search for natural or synthetic compound binders with biomedical and drug discovery purposes, i.e., with potential as antimicrobials or antiparasitics. Given that marine resources are an extraordinary source of bioactive molecules, we screened marine invertebrates for new inhibitory compounds with such capabilities. In this work, we report the isolation and molecular and functional characterization of NpCI, a novel strong metallocarboxypeptidase inhibitor from the marine snail Nerita peloronta. NpCI was purified until homogeneity using a combination of affinity chromatography and RP-HPLC. It appeared as a 5921.557 Da protein with 53 residues and six disulphide-linked cysteines, displaying a high sequence similarity with NvCI, a carboxypeptidase inhibitor isolated from Nerita versicolor, a mollusc of the same genus. The purified inhibitor was determined to be a slow- and tight-binding inhibitor of bovine CPA (Ki = 1.1·× 10[sup.−8] mol/L) and porcine CPB (Ki = 8.15·× 10[sup.−8] mol/L) and was not able to inhibit proteases from other mechanistic classes. Importantly, this inhibitor showed antiplasmodial activity against Plasmodium falciparum in an in vitro culture (IC[sub.50] = 5.5 μmol/L), reducing parasitaemia mainly by inhibiting the later stages of the parasite’s intraerythrocytic cycle whilst having no cytotoxic effects on human fibroblasts. Interestingly, initial attempts with other related proteinaceous carboxypeptidase inhibitors also displayed similar antiplasmodial effects. Coincidentally, in recent years, a metallocarboxypeptidase named PfNna1, which is expressed in the schizont phase during the late intraerythrocytic stage of the parasite’s life cycle, has been described. Given that NpCI showed a specific parasiticidal effect on P. falciparum, eliciting pyknotic/dead parasites, our results suggest that this and related inhibitors could be promising starting agents or lead compounds for antimalarial drug discovery strategies. |
doi_str_mv | 10.3390/md21020094 |
format | Article |
fullrecord | <record><control><sourceid>gale</sourceid><recordid>TN_cdi_gale_infotracmisc_A750398070</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A750398070</galeid><sourcerecordid>A750398070</sourcerecordid><originalsourceid>FETCH-LOGICAL-g670-ca91ebe5425c5a17482eb2a7c9c84e63031c4541eda6bdc9e6e46dffeded27c83</originalsourceid><addsrcrecordid>eNptkE1Lw0AQhoMoWKsXf8GCV9Nuks3XMRQ_Am0V7L1MdifNyGY3JFtr_T_-TwN66EHmMMPDM-_h9bzbgM-iKOfzVoUBDznPxZk3CZKE-yNOz0_uS-9qGN45j-IsFxPvuxysBkfWMDCKLRroQTrs6esX2pqtu0V5z4Ct8cBW6EBrK6Gv7Oexw86RggFZaRqqyNme1b1tmWuQraAng-zNAGlWrsdIB6xDbXtrHMxLdiDXsMI48stXDUNrFe1bVoOW1EG_b0elkI4-yB2vvYuRD3jzt6fe5vFhs3j2ly9P5aJY-rsk5b6EPMAKYxHGMoYgFVmIVQipzGUmMIl4FEgRiwAVJJWSOSYoElXXqFCFqcyiqXf3G7sDjVsytXVjGy0NclukMY_yjKd8tGb_WOMobElagzWN_OThB1K-f4w</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Isolation and Characterization of NpCI, a New Metallocarboxypeptidase Inhibitor from the Marine Snail INerita peloronta/I with Anti-IPlasmodium falciparum/I Activity</title><source>DOAJ Directory of Open Access Journals</source><source>PubMed Central Open Access</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Free Full-Text Journals in Chemistry</source><creator>Cabrera-Muñoz, Aymara ; Sierra-Gómez, Yusvel ; Covaleda-Cortés, Giovanni ; Reytor, Mey L ; González-González, Yamile ; Bautista, José M ; Avilés, Francesc Xavier ; Alonso-del-Rivero, Maday</creator><creatorcontrib>Cabrera-Muñoz, Aymara ; Sierra-Gómez, Yusvel ; Covaleda-Cortés, Giovanni ; Reytor, Mey L ; González-González, Yamile ; Bautista, José M ; Avilés, Francesc Xavier ; Alonso-del-Rivero, Maday</creatorcontrib><description>Metallocarboxypeptidases are zinc-dependent peptide-hydrolysing enzymes involved in several important physiological and pathological processes. They have been a target of growing interest in the search for natural or synthetic compound binders with biomedical and drug discovery purposes, i.e., with potential as antimicrobials or antiparasitics. Given that marine resources are an extraordinary source of bioactive molecules, we screened marine invertebrates for new inhibitory compounds with such capabilities. In this work, we report the isolation and molecular and functional characterization of NpCI, a novel strong metallocarboxypeptidase inhibitor from the marine snail Nerita peloronta. NpCI was purified until homogeneity using a combination of affinity chromatography and RP-HPLC. It appeared as a 5921.557 Da protein with 53 residues and six disulphide-linked cysteines, displaying a high sequence similarity with NvCI, a carboxypeptidase inhibitor isolated from Nerita versicolor, a mollusc of the same genus. The purified inhibitor was determined to be a slow- and tight-binding inhibitor of bovine CPA (Ki = 1.1·× 10[sup.−8] mol/L) and porcine CPB (Ki = 8.15·× 10[sup.−8] mol/L) and was not able to inhibit proteases from other mechanistic classes. Importantly, this inhibitor showed antiplasmodial activity against Plasmodium falciparum in an in vitro culture (IC[sub.50] = 5.5 μmol/L), reducing parasitaemia mainly by inhibiting the later stages of the parasite’s intraerythrocytic cycle whilst having no cytotoxic effects on human fibroblasts. Interestingly, initial attempts with other related proteinaceous carboxypeptidase inhibitors also displayed similar antiplasmodial effects. Coincidentally, in recent years, a metallocarboxypeptidase named PfNna1, which is expressed in the schizont phase during the late intraerythrocytic stage of the parasite’s life cycle, has been described. Given that NpCI showed a specific parasiticidal effect on P. falciparum, eliciting pyknotic/dead parasites, our results suggest that this and related inhibitors could be promising starting agents or lead compounds for antimalarial drug discovery strategies.</description><identifier>ISSN: 1660-3397</identifier><identifier>EISSN: 1660-3397</identifier><identifier>DOI: 10.3390/md21020094</identifier><language>eng</language><publisher>MDPI AG</publisher><subject>Antimalarials ; Chemical properties ; Enzyme inhibitors ; Health aspects ; Identification and classification ; Marine fauna ; Metalloenzymes ; Organic compounds ; Pharmaceutical research</subject><ispartof>Marine drugs, 2023-01, Vol.21 (2)</ispartof><rights>COPYRIGHT 2023 MDPI AG</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,864,27924,27925</link.rule.ids></links><search><creatorcontrib>Cabrera-Muñoz, Aymara</creatorcontrib><creatorcontrib>Sierra-Gómez, Yusvel</creatorcontrib><creatorcontrib>Covaleda-Cortés, Giovanni</creatorcontrib><creatorcontrib>Reytor, Mey L</creatorcontrib><creatorcontrib>González-González, Yamile</creatorcontrib><creatorcontrib>Bautista, José M</creatorcontrib><creatorcontrib>Avilés, Francesc Xavier</creatorcontrib><creatorcontrib>Alonso-del-Rivero, Maday</creatorcontrib><title>Isolation and Characterization of NpCI, a New Metallocarboxypeptidase Inhibitor from the Marine Snail INerita peloronta/I with Anti-IPlasmodium falciparum/I Activity</title><title>Marine drugs</title><description>Metallocarboxypeptidases are zinc-dependent peptide-hydrolysing enzymes involved in several important physiological and pathological processes. They have been a target of growing interest in the search for natural or synthetic compound binders with biomedical and drug discovery purposes, i.e., with potential as antimicrobials or antiparasitics. Given that marine resources are an extraordinary source of bioactive molecules, we screened marine invertebrates for new inhibitory compounds with such capabilities. In this work, we report the isolation and molecular and functional characterization of NpCI, a novel strong metallocarboxypeptidase inhibitor from the marine snail Nerita peloronta. NpCI was purified until homogeneity using a combination of affinity chromatography and RP-HPLC. It appeared as a 5921.557 Da protein with 53 residues and six disulphide-linked cysteines, displaying a high sequence similarity with NvCI, a carboxypeptidase inhibitor isolated from Nerita versicolor, a mollusc of the same genus. The purified inhibitor was determined to be a slow- and tight-binding inhibitor of bovine CPA (Ki = 1.1·× 10[sup.−8] mol/L) and porcine CPB (Ki = 8.15·× 10[sup.−8] mol/L) and was not able to inhibit proteases from other mechanistic classes. Importantly, this inhibitor showed antiplasmodial activity against Plasmodium falciparum in an in vitro culture (IC[sub.50] = 5.5 μmol/L), reducing parasitaemia mainly by inhibiting the later stages of the parasite’s intraerythrocytic cycle whilst having no cytotoxic effects on human fibroblasts. Interestingly, initial attempts with other related proteinaceous carboxypeptidase inhibitors also displayed similar antiplasmodial effects. Coincidentally, in recent years, a metallocarboxypeptidase named PfNna1, which is expressed in the schizont phase during the late intraerythrocytic stage of the parasite’s life cycle, has been described. Given that NpCI showed a specific parasiticidal effect on P. falciparum, eliciting pyknotic/dead parasites, our results suggest that this and related inhibitors could be promising starting agents or lead compounds for antimalarial drug discovery strategies.</description><subject>Antimalarials</subject><subject>Chemical properties</subject><subject>Enzyme inhibitors</subject><subject>Health aspects</subject><subject>Identification and classification</subject><subject>Marine fauna</subject><subject>Metalloenzymes</subject><subject>Organic compounds</subject><subject>Pharmaceutical research</subject><issn>1660-3397</issn><issn>1660-3397</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNptkE1Lw0AQhoMoWKsXf8GCV9Nuks3XMRQ_Am0V7L1MdifNyGY3JFtr_T_-TwN66EHmMMPDM-_h9bzbgM-iKOfzVoUBDznPxZk3CZKE-yNOz0_uS-9qGN45j-IsFxPvuxysBkfWMDCKLRroQTrs6esX2pqtu0V5z4Ct8cBW6EBrK6Gv7Oexw86RggFZaRqqyNme1b1tmWuQraAng-zNAGlWrsdIB6xDbXtrHMxLdiDXsMI48stXDUNrFe1bVoOW1EG_b0elkI4-yB2vvYuRD3jzt6fe5vFhs3j2ly9P5aJY-rsk5b6EPMAKYxHGMoYgFVmIVQipzGUmMIl4FEgRiwAVJJWSOSYoElXXqFCFqcyiqXf3G7sDjVsytXVjGy0NclukMY_yjKd8tGb_WOMobElagzWN_OThB1K-f4w</recordid><startdate>20230101</startdate><enddate>20230101</enddate><creator>Cabrera-Muñoz, Aymara</creator><creator>Sierra-Gómez, Yusvel</creator><creator>Covaleda-Cortés, Giovanni</creator><creator>Reytor, Mey L</creator><creator>González-González, Yamile</creator><creator>Bautista, José M</creator><creator>Avilés, Francesc Xavier</creator><creator>Alonso-del-Rivero, Maday</creator><general>MDPI AG</general><scope/></search><sort><creationdate>20230101</creationdate><title>Isolation and Characterization of NpCI, a New Metallocarboxypeptidase Inhibitor from the Marine Snail INerita peloronta/I with Anti-IPlasmodium falciparum/I Activity</title><author>Cabrera-Muñoz, Aymara ; Sierra-Gómez, Yusvel ; Covaleda-Cortés, Giovanni ; Reytor, Mey L ; González-González, Yamile ; Bautista, José M ; Avilés, Francesc Xavier ; Alonso-del-Rivero, Maday</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-g670-ca91ebe5425c5a17482eb2a7c9c84e63031c4541eda6bdc9e6e46dffeded27c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antimalarials</topic><topic>Chemical properties</topic><topic>Enzyme inhibitors</topic><topic>Health aspects</topic><topic>Identification and classification</topic><topic>Marine fauna</topic><topic>Metalloenzymes</topic><topic>Organic compounds</topic><topic>Pharmaceutical research</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cabrera-Muñoz, Aymara</creatorcontrib><creatorcontrib>Sierra-Gómez, Yusvel</creatorcontrib><creatorcontrib>Covaleda-Cortés, Giovanni</creatorcontrib><creatorcontrib>Reytor, Mey L</creatorcontrib><creatorcontrib>González-González, Yamile</creatorcontrib><creatorcontrib>Bautista, José M</creatorcontrib><creatorcontrib>Avilés, Francesc Xavier</creatorcontrib><creatorcontrib>Alonso-del-Rivero, Maday</creatorcontrib><jtitle>Marine drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cabrera-Muñoz, Aymara</au><au>Sierra-Gómez, Yusvel</au><au>Covaleda-Cortés, Giovanni</au><au>Reytor, Mey L</au><au>González-González, Yamile</au><au>Bautista, José M</au><au>Avilés, Francesc Xavier</au><au>Alonso-del-Rivero, Maday</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Isolation and Characterization of NpCI, a New Metallocarboxypeptidase Inhibitor from the Marine Snail INerita peloronta/I with Anti-IPlasmodium falciparum/I Activity</atitle><jtitle>Marine drugs</jtitle><date>2023-01-01</date><risdate>2023</risdate><volume>21</volume><issue>2</issue><issn>1660-3397</issn><eissn>1660-3397</eissn><abstract>Metallocarboxypeptidases are zinc-dependent peptide-hydrolysing enzymes involved in several important physiological and pathological processes. They have been a target of growing interest in the search for natural or synthetic compound binders with biomedical and drug discovery purposes, i.e., with potential as antimicrobials or antiparasitics. Given that marine resources are an extraordinary source of bioactive molecules, we screened marine invertebrates for new inhibitory compounds with such capabilities. In this work, we report the isolation and molecular and functional characterization of NpCI, a novel strong metallocarboxypeptidase inhibitor from the marine snail Nerita peloronta. NpCI was purified until homogeneity using a combination of affinity chromatography and RP-HPLC. It appeared as a 5921.557 Da protein with 53 residues and six disulphide-linked cysteines, displaying a high sequence similarity with NvCI, a carboxypeptidase inhibitor isolated from Nerita versicolor, a mollusc of the same genus. The purified inhibitor was determined to be a slow- and tight-binding inhibitor of bovine CPA (Ki = 1.1·× 10[sup.−8] mol/L) and porcine CPB (Ki = 8.15·× 10[sup.−8] mol/L) and was not able to inhibit proteases from other mechanistic classes. Importantly, this inhibitor showed antiplasmodial activity against Plasmodium falciparum in an in vitro culture (IC[sub.50] = 5.5 μmol/L), reducing parasitaemia mainly by inhibiting the later stages of the parasite’s intraerythrocytic cycle whilst having no cytotoxic effects on human fibroblasts. Interestingly, initial attempts with other related proteinaceous carboxypeptidase inhibitors also displayed similar antiplasmodial effects. Coincidentally, in recent years, a metallocarboxypeptidase named PfNna1, which is expressed in the schizont phase during the late intraerythrocytic stage of the parasite’s life cycle, has been described. Given that NpCI showed a specific parasiticidal effect on P. falciparum, eliciting pyknotic/dead parasites, our results suggest that this and related inhibitors could be promising starting agents or lead compounds for antimalarial drug discovery strategies.</abstract><pub>MDPI AG</pub><doi>10.3390/md21020094</doi></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1660-3397 |
ispartof | Marine drugs, 2023-01, Vol.21 (2) |
issn | 1660-3397 1660-3397 |
language | eng |
recordid | cdi_gale_infotracmisc_A750398070 |
source | DOAJ Directory of Open Access Journals; PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
subjects | Antimalarials Chemical properties Enzyme inhibitors Health aspects Identification and classification Marine fauna Metalloenzymes Organic compounds Pharmaceutical research |
title | Isolation and Characterization of NpCI, a New Metallocarboxypeptidase Inhibitor from the Marine Snail INerita peloronta/I with Anti-IPlasmodium falciparum/I Activity |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T02%3A24%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Isolation%20and%20Characterization%20of%20NpCI,%20a%20New%20Metallocarboxypeptidase%20Inhibitor%20from%20the%20Marine%20Snail%20INerita%20peloronta/I%20with%20Anti-IPlasmodium%20falciparum/I%20Activity&rft.jtitle=Marine%20drugs&rft.au=Cabrera-Mu%C3%B1oz,%20Aymara&rft.date=2023-01-01&rft.volume=21&rft.issue=2&rft.issn=1660-3397&rft.eissn=1660-3397&rft_id=info:doi/10.3390/md21020094&rft_dat=%3Cgale%3EA750398070%3C/gale%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/&rft_galeid=A750398070&rfr_iscdi=true |