Bestatin is a non-competitive inhibitor of porcine M1 family glutamyl aminopeptidase: Insights for selective inhibitor design

Glutamyl aminopeptidase (APA) is an M1 family membrane-bound ectoenzyme that is a target for the development of antihypertensive and anticancer agents. Bestatin is a natural product described as a classical inhibitor of metallo-aminopeptidases. Although the IC50 value of bestatin vs human APA has been reported, the mechanism of inhibition is unknown. In the present contribution, we demonstrated that bestatin is a non-competitive (α>1) inhibitor of porcine APA (pAPA), with a Ki value of 31.59 µM (α=3.7). A model of the bestatin-pAPA complex predicted that bestatin binds to pAPA similarly to porcine aminopeptidase N (pAPN). The interaction involved catalytic and chelating residues conserved in the M1 family. Additionally, a salt bridge with R877 and a hydrogen bond interaction with T346, both key residues for APA specificity for N-terminal acidic residues were identified. These residues and E213, which forms a hydrogen bond interaction with bestatin, are not conserved in human and porcine APN. The extension of the in silico analysis to amastatin and bestatin analogs probestin, and phebestin, which are APA inhibitors, indicated that they may interact with the same residues. The results indicate that bestatin analogues currently reported to inhibit APN are dual inhibitors of APA and APN and that some APA residues could be targeted to improve inhibitor selectivity

Bestatin is a non-competitive inhibitor of porcine M1 family glutamyl aminopeptidase: Insights for selective inhibitor design

173-180Glutamyl aminopeptidase (APA) is an M1 family membrane-bound ectoenzyme that is a target for the development of antihypertensive and anticancer agents. Bestatin is a natural product described as a classical inhibitor of metallo-aminopeptidases. Although the IC50 value of bestatin vs human APA has been reported, the mechanism of inhibition is unknown. In the present contribution, we demonstrated that bestatin is a non-competitive (α>1) inhibitor of porcine APA (pAPA), with a Ki value of 31.59 μM (α=3.7). A model of the bestatin-pAPA complex predicted that bestatin binds to pAPA similarly to porcine aminopeptidase N (pAPN). The interaction involved catalytic and chelating residues conserved in the M1 family. Additionally, a salt bridge with R877 and a hydrogen bond interaction with T346, both key residues for APA specificity for N-terminal acidic residues were identified. These residues and E213, which forms a hydrogen bond interaction with bestatin, are not conserved in human and porcine APN. The extension of the in silico analysis to amastatin and bestatin analogs probestin, and phebestin, which are APA inhibitors, indicated that they may interact with the same residues. The results indicate that bestatin analogues currently reported to inhibit APN are dual inhibitors of APA and APN and that some APA residues could be targeted to improve inhibitor selectivity

advice from the scientific advisory board of the organisation for the prohibition of chemical weapons on isotopically labelled chemicals and stereoisomers in relation to the chemical weapons convention

AbstractThe Chemical Weapons Convention (CWC) is an international disarmament treaty that prohibits the development, stockpiling and use of chemical weapons. This treaty has 193 States Parties (nations for which the treaty is binding) and entered into force in 1997. The CWC contains schedules of chemicals that have been associated with chemical warfare programmes. These scheduled chemicals must be declared by the States that possess them and are subject to verification by the Organisation for the Prohibition of Chemical Weapons (OPCW, the implementing body of the CWC). Isotopically labelled and stereoisomeric variants of the scheduled chemicals have presented ambiguities for interpretation of the requirements of treaty implementation, and advice was sought from the OPCW's Scientific Advisory Board (SAB) in 2016. The SAB recommended that isotopically labelled compounds or stereoisomers related to the parent compound specified in a schedule should be interpreted as belonging to the same schedule. This advice should benefit scientists and diplomats from the CWC's State Parties to help ensure a consistent approach to their declarations of scheduled chemicals (which in turn supports both the correctness and completeness of declarations under the CWC). Herein, isotopically labelled and stereoisomeric variants of CWC-scheduled chemicals are reviewed, and the impact of the SAB advice in influencing a change to national licensing in one of the State Parties is discussed. This outcome, an update to national licensing governing compliance to an international treaty, serves as an example of the effectiveness of science diplomacy within an international disarmament treaty

innovative technologies for chemical security

AbstractAdvances across the chemical and biological (life) sciences are increasingly enabled by ideas and tools from sectors outside these disciplines, with information and communication technologies playing a key role across 21st century scientific development. In the face of rapid technological change, the Organisation for the Prohibition of Chemical Weapons (OPCW), the implementing body of the Chemical Weapons Convention ("the Convention"), seeks technological opportunities to strengthen capabilities in the field of chemical disarmament. The OPCW Scientific Advisory Board (SAB) in its review of developments in science and technology examined the potential uses of emerging technologies for the implementation of the Convention at a workshop entitled "Innovative Technologies for Chemical Security", held from 3 to 5 July 2017, in Rio de Janeiro, Brazil. The event, organized in cooperation with the International Union of Pure and Applied Chemistry (IUPAC), the National Academies of Science, Engineering and Medicine of the United States of America, the Brazilian Academy of Sciences, and the Brazilian Chemical Society, was attended by 45 scientists and engineers from 22 countries. Their insights into the use of innovative technological tools and how they might benefit chemical disarmament and non-proliferation informed the SAB's report on developments in science and technology for the Fourth Review Conference of the Convention (to be held in November 2018), and are described herein, as are recommendations that the SAB submitted to the OPCW Director-General and the States Parties of the Convention. It is concluded that technologies exist or are under development that could be used for investigations, contingency, assistance and protection, reducing risks to inspectors, and enhancing sampling and analysis

A Comprehensive Review of Patented Antimicrobial Peptides from Amphibian Anurans

Since the 1980s, studies of antimicrobial peptides (AMPs) derived from anuran skin secretions have unveiled remarkable structural diversity and a wide range of activities. This study explores the potential of these peptides for drug development by examining granted patents, amino acid modifications related to patented peptides, and recent amphibians’ taxonomic updates influencing AMP names. A total of 188 granted patents related to different anuran peptides were found, with Asia and North America being the predominant regions, contributing 65.4% and 15.4%, respectively. Conversely, although the Neotropical region is the world’s most diversified region for amphibians, it holds only 3.7% of the identified patents. The antimicrobial activities of the peptides are claimed in 118 of these 188 patents. Additionally, for 160 of these peptides, 66 patents were registered for the natural sequence, 69 for both natural and derivative sequences, and 20 exclusively for sequence derivatives. Notably, common modifications include alterations in the side chains of amino acids and modifications to the peptides’ N- and C-termini. This review underscores the biomedical potential of anuran-derived AMPs, emphasizing the need to bridge the gap between AMP description and practical drug development while highlighting the urgency of biodiversity conservation to facilitate biomedical discoveries

Aqueous extracts of marine invertebrates from Cuba coastline display neutral aminopeptidase inhibitory activities and effects on cancer cells and <i>Plasmodium falciparum</i> parasites

107-119Neutral aminopeptidases are enzymes distributed in all living organisms. By hydrolyzing biologically active peptides in tissues and biological fluids, they are involved in the control of many physiological processes. They became established targets for new therapeutic agents in cancer, but also in parasitic diseases like malaria. Marine organisms are promising sources for biomolecules but few examples of neutral aminopeptidase inhibitors are described. The goal of this work was to search in Cuban marine invertebrates, for inhibitory activities of neutral aminopeptidases of biomedical relevance, belonging to the M1 and M17 metallopeptidase families. The screening of inhibitory activities was performed using aqueous crude extracts and their 2.5 % TCA treatments. The treatments with 2.5 % TCA increased the recovery of inhibitory activities versus all enzymes tested and from all of marine species. These inhibitory activities were dose-dependent in all cases, with certain selectivity for PfA-M17 regarding hLAP, and good inhibition of hAPN. Interestingly, some TCA treated extracts displayed promising effect on either Plasmodium parasite growth as well as on PC3 and 3LL cells. This contribution is the first report identifying inhibitory activities from marine invertebrates, directed against human and malarial neutral aminopeptidases, suggesting a potential for biomedical applications for the corresponding marine species

Aqueous extracts of marine invertebrates from Cuba coastline display neutral aminopeptidase inhibitory activities and effects on cancer cells and Plasmodium falciparum parasites

Neutral aminopeptidases are enzymes distributed in all living organisms. By hydrolyzing biologically active peptides in tissues and biological fluids, they are involved in the control of many physiological processes. They became established targets for new therapeutic agents in cancer, but also in parasitic diseases like malaria. Marine organisms are promising sources for biomolecules but few examples of neutral aminopeptidase inhibitors are described. The goal of this work was to search in Cuban marine invertebrates, for inhibitory activities of neutral aminopeptidases of biomedical relevance, belonging to the M1 and M17 metallopeptidase families. The screening of inhibitory activities was performed using aqueous crude extracts and their 2.5 % TCA treatments. The treatments with 2.5 % TCA increased the recovery of inhibitory activities versus all enzymes tested and from all of marine species. These inhibitory activities were dose-dependent in all cases, with certain selectivity for PfA-M17 regarding hLAP, and good inhibition of hAPN. Interestingly, some TCA treated extracts displayed promising effect on either Plasmodium parasite growth as well as on PC3 and 3LL cells. This contribution is the first report identifying inhibitory activities from marine invertebrates, directed against human and malarial neutral aminopeptidases, suggesting a potential for biomedical applications for the corresponding marine species

La investigación científica en el campo de la malaria, importancia socioeconómica y ética

Objetivo: Analizar el impacto socioeconómico y ético de la investigación científica dirigida a la búsqueda de nuevos antimaláricos. Desarrollo: En este trabajo se aborda el problema de la malaria en la última década en sus aspectos epidemiológico, económico, social, ético, de investigación, y de la posición de la ciencia cubana. La malaria es una enfermedad parasitaria que constituye un problema de salud global por motivos científicos, sociales, económicos y éticos. Los países subdesarrollados son los más afectados, con una elevada morbilidad y mortalidad, sistemas de salud saturados y economías sobrecargadas. La malaria pertenece al grupo de las enfermedades desatendidas, quienes han constituido por siglos una gran carga para los países pobres con un impacto directo negativo en el desarrollo de estas sociedades. La implementación de nuevas estrategias más económicas, sencillas, sostenibles y localmente aceptables para mejorar la salud de las poblaciones olvidadas, significaría una contribución notable a la prevención, control y eliminación de esta y otras enfermedades desatendidas. Conclusiones: La investigación científica dirigida a la búsqueda de nuevos antimaláricos es una necesidad urgente, sobre todo en los países tropicales. La malaria afecta en mayor medida a los países del Tercer Mundo, los cuales no tienen posibilidades reales de financiar programas de investigación y salud sostenibles, y verdaderamente efectivos que garanticen una amplia cobertura a su población