Thimet oligopeptidase (TOP, EC 3.4.24.15) and neurolysin (NEL, EC 3.4.24.16) are closely related zinc-dependent metalo-oligopeptidases, which take part in the metabolism of oligopeptides (from 5 to 17 amino acid residues) inside and outside cells. Both peptidases are ubiquitously distributed in tissues. TOP is one of the main intracellular peptide-processing enzymes being important for the antigen selection in the MHC Class I presentation route, while NEL function has been more associated with the extracellular degradation of neurotensin. Despite efforts being made to develop specific inhibitors for these peptidases, the most used are: CPP-Ala-Ala-Tyr-PABA, described by Orlowski et al. in 1988, and CPP-Ala-Aib-Tyr-PABA (JA-2) that is an analog more resistant to proteolysis, which development was made by Shrimpton et al. in 2000. In the present work, we describe other analogs of these compounds but, with better discriminatory capacity to inhibit specifically NEL or TOP. The modifications introduced in these new analogs were based on a key difference existent in the extended binding sites of NEL and TOP: the negatively charged Glu residue of TOP corresponds to the positively charged Arg residue of NEL. These residues are in position to interact with the residue at the P' and/or P' of their substrates (mimicked by the Ala-Ala/P1'-P2' residues of the CPP-Ala-Ala-Tyr-PABA). Therefore, exploring this single difference, the following compounds were synthesized: CPP-Asp-Ala-Tyr-PABA, CPP-Arg-Ala-Tyr-PABA, CPP-Ala-Asp-Tyr-PABA, CPP-Ala-Arg-Tyr-PABA. Confirming the predictions, the replacement of each non-charged residue of the internal portion Ala-Ala by a charged residue Asp or Arg resulted in compounds with higher selectivity for NEL or TOP, especially due to the electrostatic attraction or repulsion by the NEL Arg or TOP Glu residue. The CPP-Asp-Ala-Tyr-PABA and CPP-Ala-Asp-Tyr-PABA presented higher affinities for NEL, and, the CFP-Ala-Arg-Tyr-PABA showed higher affinity for TOP.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbrc.2019.11.097 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Multilevel semantic and adaptive actionness learning for weakly supervised temporal action localization.
Neural Netw
February 2025
National Engineering Laboratory for Brain-inspired Intelligence Technology and Application (NEL-BITA), University of Science and Technology of China, Hefei, 230026, China. Electronic address:
Weakly supervised temporal action localization aims to identify and localize action instances in untrimmed videos with only video-level labels. Typically, most methods are based on a multiple instance learning framework that uses a top-K strategy to select salient segments to represent the entire video. Therefore fine-grained video information cannot be learned, resulting in poor action classification and localization performance.
View Article and Find Full Text PDFNickel Phosphide: The Effect of Phosphorus Content on the Activity and Stability toward Oxygen Evolution Reaction in Alkaline Medium.
ChemSusChem
January 2025
Department of Materials Science and Engineering, Norwegian University of Science and Technology (NTNU), Trondheim, N-7491, Norway.
In this work a systematic study of the effect of the metal to phosphorus ratio in Ni-P nanoparticles on their catalytic activity with respect to the OER is reported. To this end, nickel phosphide nanoparticles are synthesized through two different synthesis routes, one involving in-situ phosphidation and one involving ex-situ phosphidation. In-situ phosphidation is performed via two steps route in a one-pot synthesis, in which Ni nanoparticles are formed at 220 °C, but not isolated, and then transformed to phase-pure either NiP or NiP nanocrystallites.
View Article and Find Full Text PDFRecognition and normalization of multilingual symptom entities using in-domain-adapted BERT models and classification layers.
Database (Oxford)
August 2024
Departamento de Lenguajes y Ciencias de la Computación, Universidad de Málaga, Blvr. Louis Pasteur, 35, Puerto de la Torre, Málaga 29071, Spain.
Due to the scarcity of available annotations in the biomedical domain, clinical natural language processing poses a substantial challenge, especially when applied to low-resource languages. This paper presents our contributions for the detection and normalization of clinical entities corresponding to symptoms, signs, and findings present in multilingual clinical texts. For this purpose, the three subtasks proposed in the SympTEMIST shared task of the Biocreative VIII conference have been addressed.
View Article and Find Full Text PDFConfusing cause and effect in public health policy.
Neuro Endocrinol Lett
April 2024
Professor Public Health St. Elisabeth University Bratislava, Slovakia.
When studying the literature on current public health policy challenges, a number of rankings can be found, created from data collected and processed by different methods and from different sources, ordering the challenges by their significance. Inevitably, in global studies, there are errors caused by averaging data across populations that differ significantly in population size and the causes of the decline in disability-adjusted life years (DALYs), potentially in combination with years of life lost (YLL) and years of life lived with disability (YLD), that may serve as indicators of the health status of a given population (Lopez 2005). Averaging data from populations that differ significantly in size, the larger population dominates and the main causes of health problems may be the same in both populations, and malnutrition and infectious diseases should be targeted, although in the smaller population cardiovascular disease is the main risk.
View Article and Find Full Text PDFHumoral immunoprofiling identifies novel biomarkers and an immune suppressive autoantibody phenotype at the site of disease in pancreatic ductal adenocarcinoma.
Front Oncol
February 2024
Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous cancer, with minimal response to therapeutic intervention and with 85% of cases diagnosed at an advanced stage due to lack of early symptoms, highlighting the importance of understanding PDAC immunology in greater detail. Here, we applied an immunoproteomic approach to investigate autoantibody responses against cancer-testis and tumor-associated antigens in PDAC using a high-throughput multiplexed protein microarray platform, comparing humoral immune responses in serum and at the site of disease in order to shed new light on immune responses in the tumor microenvironment. We simultaneously quantified serum or tissue IgG and IgA antibody isotypes and subclasses in a cohort of PDAC, disease control and healthy patients, observing inter alia that subclass utilization in tumor tissue samples was predominantly immune suppressive IgG4 and inflammatory IgA2, contrasting with predominant IgG3 and IgA1 subclass utilization in matched sera and implying local autoantibody production at the site of disease in an immune-tolerant environment.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!