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Retapamulin
Published in Anton C. de Groot, Monographs in Contact Allergy, 2021
Retapamulin is a semisynthetic pleuromutilin antibiotic. This drug is usually bacteriostatic in action, but may become bactericidal at higher concentrations. It inhibits protein synthesis by (I) binding a component of the bacterial ribosome that affects normal 50S subunit formation, (II) blocking ribosomal P-site interactions, and (III) inhibiting peptidyl transferase. The interaction with bacterial ribosomes is unique from other topical antibiotics and prevents cross-resistance (3). Retapamulin is indicated for the topical treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes and secondarily infected traumatic lesions (1).
Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Selective toxicity against bacteria can be achieved in drugs that target ribosomal RNA, and inhibiting different stages of the translation process, due to the fact that prokaryotic ribosomes differ in structure to those found in eukaryotic cells. The bacterial ribosome is a 70S particle, composed of a 30S subunit which binds to mRNA and initiates protein synthesis, and a 50S subunit, which binds to the 30S-mRNA complex to make the ribosome. The ribosome has two main binding sites: the peptide site (P site) binds the tRNA bearing the peptide chain, and the acceptor aminoacyl site (A site) binds the tRNA bearing the next amino acid in the protein sequence, to which the peptide chain will be transferred. Eukaryotic cells have bigger ribosomes made of a 60S large subunit and a 40S small subunit.
Retapamulin
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Retapamulin is a semisynthetic pleuromutilin derivative of Clitopilus scyphoides (Yan et al., 2006). Pleuromutilin is a natural product initially identified from two Basidiomycota species, Pleurotus mutilus (or C. scyphoides) and Pleurotus passeckeranius (Kavanagh et al., 1951). Pleuromutilin was shown to have activity against Gram-positive cocci and fastidious Gram-negative organism such as Haemophilus influenzae and Moraxella catarrhalis (Szybalski, 1954). Synthetic derivatives of pleuromutilin, with focus on the C(14) side chain, were generated in an attempt to improve antimicrobial activity. Retapamulin was developed by GlaxoSmithKline and has the full chemical name (1S,2R,3S,4S,6R,7R,8R,14R)-4-ethenyl-3-hydroxy-2,4,7,14tetramethyl-9-oxotricyclo[5.4.3.01,8]tetradec-6-yl([{3-exo}-8-methyl-8 azabicyclo{3.2.1}oct-3yl]thio) acetate (EMA, 2007); its empiric molecular formula is C30H47NO4S, its molecular weight is 517.7703, and the chemical structure is shown in Figure 90.1. Retapamulin has a unique mode of action that involves interaction with ribosomal protein L3 at a binding site in the regions of the ribosomal P site. Binding results in partial blocking of the P site and inhibition of peptidyl transfer, which prevents normal formation of the active 50S ribosomal subunit and thereby selective inhibition of bacterial protein synthesis (Yan et al., 2006).
Proteomic repository data submission, dissemination, and reuse: key messages
Published in Expert Review of Proteomics, 2022
In addition to GPMDB and PeptideAtlas, other novel resources have been recently created with a special focus on PTM evidence from MS-based public data: Scop3P [17], MassIVE-KB [24] or PRIDE Peptidome [5]. Scop3P (https://iomics.ugent.be/scop3p/) integrates sequences (UniProtKB/Swiss-Prot), sequence structures (PDB), and uniformly reprocessed phosphoproteomics data (PRIDE) to annotate all known human phosphosites. The ionbot search engine, which uses MS2Rescore and MS2PIP to boost the number of peptide identifications, was used to reanalyze more than 30 phosphoproteomics datasets from the PRIDE database. The Scope3P workflow uses the PhosphoRS algorithm [55] to compute the localization probability for the P-sites. If there are multiple peptide spectrum matches (PSMs) or multiple peptides for a given P-site, then the P-site was only included if a site probability of at least 0.5 was found in at least one of these identifications. The Scop3P web interface allows queries by protein accession or PX accession to navigate the phospho evidence for each protein. Figure 3(c) presents a Venn diagram of the number of phospho-sites present in PeptideAtlas compared with Scop3P. While both resources shared 36,546 phospho peptides, PeptideAtlas contains 45’908 unique phosphopeptides, while Scop3P stores 36,885 unique evidence.
Potential alternatives to current cholinesterase inhibitors: an in silico drug repurposing approach
Published in Drug Development and Industrial Pharmacy, 2021
Debanjan Kundu, Vikash Kumar Dubey
On the other hand, based on this study, we can hypothesize that both Brexipiprazole and Pimavanserin form strong interactions with key residues of the butyrylcholinesterase enzyme compared to Donepezil. Our molecular docking results indicated that both Pimavanserin and Brexipirazole could follow similar mechanisms of inhibition of these enzymes. The drug molecules form a hydrogen bond with residues Gly116 and Gly117, which form the oxyanion hole similar to acetylcholinesterase. Further, these molecules also show interactions with Asp70, which forms the P-site. Interactions of molecules with these residue implies blocking of product release and further reduces enzymatic activity. Pimavanserin and Brexipirazole shows hydrophobic as well as Pi-stacking interactions with another critical residue, Tyr332. This residue is known to bind to both the substrate and inhibitor. Interaction of the drugs with these residues implies that they can compete with the substrate and reduce the substrate’s access to the active site, further altering the efficiency through any conformational change. These molecules also show strong interactions with active site residues, including Ser198 and His438, thus implying direct inhibitory activity toward the enzyme. Our simulation analysis also indicated that Brexipirazole could be a better candidate than Pimavanserin, as it showed significantly lower energy compared to both Donepezil and Pimavanserin (Table 6). The other analyses also showed a better impact of Brexipiprazole on the enzyme, as shown in our RMSD and Radius of gyration results.
Translational readthrough inducing drugs for the treatment of inherited retinal dystrophies
Published in Expert Review of Ophthalmology, 2020
Christopher M Way, Dulce Lima Cunha, Mariya Moosajee
During translation, the ribosomal A-site can interact with near-cognate codons [44]. At all termination codons, there is competition between the termination complex and near-cognate aminoacyl-tRNAs. If a near-cognate tRNA outcompetes the termination complex, tRNA complex translocates to the P-site and translation continues [45,46] (Figure 1(c)). This occurs endogenously but at a very low frequency (between 0.01% and 0.1%), due to the three-dimensional configuration of the ribosome and key signaling proteins such as PABP [47,48]. Endogenous readthrough of a PTC is more common (increasing to <1%) as the ribosomal pausing facilitates more aminoacyl-tRNA sampling [49]. However, this is not in sufficient levels to restore protein function. Nonsense suppression therapy uses translational readthrough-inducing drugs (TRIDs) to efficiently identify and readthrough PTCs alone, resulting in the production of full-length protein.