ricin Dotaz Zobrazit nápovědu
Ricín je mimoriadne toxický lektín typu RIP II. Jeho jedovatosť je možné zneužiť na teroristickéúčely, pričom nie je zatiaľ známy efektívny protijed. Mechanizmus toxického pôsobenia je zároveňštudovaný s cieľom prípravy selektívnych imunotoxínov, ktoré by sa dali použiť pri liečbe rôznychtypov rakoviny či HIV infekcie. Napriek sľubným in vitro výsledkom, nepriaznivé vedľajšie účinkyv pokusoch in vivo zatiaľ obmedzujú ich použitie v reálnej terapii.
Ricin is a very toxic RIP II type lectin.As no effective antidote is known, its toxicity could be misusedin terrorist actions. The mechanism of the toxic action is currently studied for the preparation ofselective immunotoxins, which could be used in the therapy of various cancer diseases or HIVinfection. There are promising in vitro results, but some adverse in vivo effects limit the use of thesepreparations in real therapy.
- MeSH
- biologické toxiny chemie škodlivé účinky MeSH
- lidé MeSH
- monoklonální protilátky farmakologie chemie terapeutické užití MeSH
- otrava etiologie terapie MeSH
- ricin chemie škodlivé účinky MeSH
- ricinový olej chemie terapeutické užití toxicita MeSH
- Ricinus MeSH
- vztahy mezi strukturou a aktivitou terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
The castor plant (Ricinus communis) is primarily known for its seeds, which contain a unique fatty acid called ricinoleic acid with several industrial and commercial applications. Castor seeds also contain ricin, a toxin considered a chemical and biological warfare agent. Despite years of investigation, there is still no effective antidote or vaccine available. However, some progress has been made, and the development of an effective treatment may be on the horizon. To provide an updated overview of this issue, we have conducted a comprehensive review of the literature on the current state of research in the fight against ricin. This review is based on the reported research and aims to address the challenges faced by researchers, as well as highlight the most successful cases achieved thus far. Our goal is to encourage the scientific community to continue their efforts in this critical search.
- MeSH
- antidota * chemie farmakologie MeSH
- chemické bojové látky chemie MeSH
- lidé MeSH
- ricin * antagonisté a inhibitory chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- MeSH
- jedovaté rostliny MeSH
- jedy MeSH
- lidé MeSH
- ricin aplikace a dávkování škodlivé účinky MeSH
- semena rostlinná MeSH
- Check Tag
- lidé MeSH
We report for the first time the efficient use of accelerated solvent extraction (ASE) for extraction of ricin to analytical purposes, followed by the combined use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and MALDI-TOF MS/MS method. That has provided a fast and unambiguous method of ricin identification for in real cases of forensic investigation of suspected samples. Additionally, MALDI-TOF MS was applied to characterize the presence and the toxic activity of ricin in irradiated samples. Samples containing ricin were subjected to ASE, irradiated with different dosages of gamma radiation, and analyzed by MALDI-TOF MS/MS for verification of the intact protein signal. For identification purposes, samples were previously subjected to SDS-PAGE, for purification and separation of the chains, followed by digestion with trypsin, and analysis by MALDI-TOF MS/MS. The results were confirmed by verification of the amino acid sequences of some selected peptides by MALDI-TOF MS/MS. The samples residual toxic activity was evaluated through incubation with a DNA substrate, to simulate the attack by ricin, followed by MALDI-TOF MS/MS analyses.
- MeSH
- aceton chemie MeSH
- elektroforéza v polyakrylamidovém gelu MeSH
- hexany chemie MeSH
- peptidy analýza chemie MeSH
- ricin analýza chemie MeSH
- rozpouštědla chemie MeSH
- sekvence aminokyselin MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- tandemová hmotnostní spektrometrie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Ricin is a potent cytotoxin with no available antidote. Its catalytic subunit, RTA, damages the ribosomal RNA (rRNA) of eukaryotic cells, preventing protein synthesis and eventually leading to cell death. The combination between easiness of obtention and high toxicity turns ricin into a potential weapon for terrorist attacks, urging the need of discovering effective antidotes. On this context, we used computational techniques, in order to identify potential ricin inhibitors among approved drugs. Two libraries were screened by two different docking algorithms, followed by molecular dynamics simulations and MM-PBSA calculations in order to corroborate the docking results. Three drugs were identified as potential ricin inhibitors: deferoxamine, leucovorin and plazomicin. Our calculations showed that these compounds were able to, simultaneously, form hydrogen bonds with residues of the catalytic site and the secondary binding site of RTA, qualifying as potential antidotes against intoxication by ricin.Communicated by Ramaswamy H. Sarma.
Explicit solvent molecular dynamics (MD) simulations were carried out for sarcin-ricin domain (SRD) motifs from 23S (Escherichia coli) and 28S (rat) rRNAs. The SRD motif consists of GAGA tetraloop, G-bulged cross-strand A-stack, flexible region and duplex part. Detailed analysis of the overall dynamics, base pairing, hydration, cation binding and other SRD features is presented. The SRD is surprisingly static in multiple 25 ns long simulations and lacks any non-local motions, with root mean square deviation (r.m.s.d.) values between averaged MD and high-resolution X-ray structures of 1-1.4 A. Modest dynamics is observed in the tetraloop, namely, rotation of adenine in its apex and subtle reversible shift of the tetraloop with respect to the adjacent base pair. The deformed flexible region in low-resolution rat X-ray structure is repaired by simulations. The simulations reveal few backbone flips, which do not affect positions of bases and do not indicate a force field imbalance. Non-Watson-Crick base pairs are rigid and mediated by long-residency water molecules while there are several modest cation-binding sites around SRD. In summary, SRD is an unusually stiff rRNA building block. Its intrinsic structural and dynamical signatures seen in simulations are strikingly distinct from other rRNA motifs such as Loop E and Kink-turns.
- MeSH
- endoribonukleasy metabolismus MeSH
- Escherichia coli genetika MeSH
- financování organizované MeSH
- fungální proteiny metabolismus MeSH
- kationty chemie MeSH
- konformace nukleové kyseliny MeSH
- krysa rodu rattus MeSH
- krystalografie rentgenová MeSH
- molekulární modely MeSH
- párování bází MeSH
- počítačová simulace MeSH
- ricin metabolismus MeSH
- RNA ribozomální 23S chemie metabolismus MeSH
- RNA ribozomální 28S chemie metabolismus MeSH
- sacharidy chemie MeSH
- vazebná místa MeSH
- voda chemie MeSH
- vodíková vazba MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.
- MeSH
- algoritmy MeSH
- chemické bojové látky chemie MeSH
- ligandy MeSH
- molekulární konformace MeSH
- molekulární struktura MeSH
- objevování léků MeSH
- ricin antagonisté a inhibitory chemie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
