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The Emerging Field of RNA Nanotechnology
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
The most challenging aspect of RNA therapeutics is the yield and cost of RNA production. Commercial RNA chemical synthesis can only offer 40 (conservative) to 80 (with low yield) nucleotides. Acetalester 2′ -OH protecting groups, such as pivaloyloxymethyl, have been reported to enhance chemical synthesis of RNA. RNase ligase II has been shown to be a good alternative over the traditional T4 DNA ligase to generate longer RNA by ligation of two shorter synthetic RNA fragments [115]. In enzymatic synthesis, heterogeneity of the 3′ -end has been an issue [116]; this can be addressed by extending the transcribed sequence beyond the intended end and then cleaving the RNA at the desired site using ribozymes, DNAzymes, or RNase H [115–117]. Large scale RNA complexes produced in bacteria escorted by a tRNA vector have also been reported [40, 41]. Based on the rapid reduction of cost over the history of DNA synthesis, it is expected that the cost of RNA synthesis will gradually decrease with the development of industrial-scale RNA production technologies.
High-Performance Liquid Chromatography
Published in Adorjan Aszalos, Modern Analysis of Antibiotics, 2020
Joel J. Kirschbaum, Adorjan Aszalos
Bacmecillinam and pivmecillinam are the 1’-ethoxycarboxyloxyethyl and pivaloyloxymethyl esters, respectively, of amdinocillin (formally known as mecillinam). Although bacmecillinam is 30% hydrolyzed in whole blood within 1 min at 37°C, it was quantified using a 5-µm octadecylsilane filled, glass-lined, steel column (100×4 mm) and a mobile phase of phosphate buffer pH 6 (ionic strength = 0.05)-acetonitrile (6:4) containing 0.001 M N-hexyl-N-methylamine [186]. Detection was at 230 nm. Recoveries averaged 98% after administration to humans. The limit of detection was 600 pg/ml.
Mecillinam (Amdinocillin) and Pivmecillinam
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
Mecillinam, developed by Leo Pharmaceutical Laboratories (Ballerup, Denmark), has a beta-lactam structure and is derived from the penicillin nucleus, 6-aminopenicillinic acid (6-APA). Natural and semisynthetic penicillins are acylamino-penicillinates, but mecillinam is a different penicillin, being a 6-beta-amidinopenicillanic acid, which contains a substituted amidino group (Lund and Tybring, 1972; Matsuhashi et al., 1974). Mecillinam, in its hydrochloride dihydrate form, is suitable for i.m. or i.v. administration, but it is not absorbed when given orally. A pivaloyloxymethyl ester of the drug, pivmecillinam hydrochloride, is readily absorbed from the gastrointestinal tract. After absorption, it is hydrolyzed by enzymes with the liberation of mecillinam, the active form of the drug (Roholt et al., 1975). A combination of pivmecillinam and the pivaloyl ester of ampicillin, pivampicillin, was used during the 1980s, but is not available today. The chemical structure of mecillinam is shown in Figure 11.1.
Modeling percutaneous absorption for successful drug discovery and development
Published in Expert Opinion on Drug Discovery, 2020
Hanumanth Srikanth Cheruvu, Xin Liu, Jeffrey E. Grice, Michael S. Roberts
However, the use of penetration modifiers may alter the absorption of undesired solutes along with the active drug that may cause skin damage or irritancy. Consequently, it may be preferable to modify a poorly penetrating drug by a chemical reaction to produce a better penetrant. This enables an inactive parent drug to be readily partitioned into the skin and subsequently converted into an active metabolite drug by skin metabolism. This delivery technique is known as prodrug therapy. For instance, pivampicillin (logP: 1.43), a pivaloyloxymethyl ester of ampicillin, is used as a prodrug for ampicillin (logP: 0.88). Here, the parent prodrug is more lipophilic than the active drug, resulting in enhanced permeation.
An overview of ProTide technology and its implications to drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Michaela Serpi, Fabrizio Pertusati
Replacement of the phosphate moiety with an isosteric and isoelectronic phosphonate group, results in a nucleoside phosphonate, (NP) a chemically and enzymatically more stable compound than the corresponding phosphate [83]. Differently from the O-P linkage, the CH2-P-bond, due to its chemical nature, is not susceptible to the hydrolytic action of phosphodiesterase and phosphatase. Like their monophosphate counterpart, a nucleoside phosphonate analog needs to be further phosphorylated by cellular nucleotide kinases. These stable phosphonate analogues, mimicking the nucleoside monophosphates, can bypass the initial (slow) enzymatic phosphorylation and be more effective antiviral agents. This approach has led to the discovery of acyclic nucleoside phosphonates (ANPs), one of the most successful class of antivirals molecules ever discovered [84]. ANPs, pioneered by the Holý group in the 1980s, were found to exhibit a broad spectrum of antiviral activities, particularly against DNA viruses and retroviruses [85,86]. Two ANPs prodrugs, the bis (pivaloyloxymethyl) ester of adefovir (bis-(POM)-PMEA; Hepsera®), and the diisopropyloxycarbonyloxymethyl ester of tenofovir fumarate (bis-(POC)-(R)-PMPA fumarate; Viread®), were approved respectively for the treatment of HBV and HIV infections. However, their toxicity, caused by the release of decomposition products, generated some concern. This prompted more research devoted to identify a better and safer ANP prodrug [10]. In this context, McGuigan’s laboratory was the first to apply the ProTide technology to ANPs [35]. In this study, the phenyloxy phosphonamidate (with L-alanine methyl ester) prodrugs of adefovir and tenofovir showed to have a superior antiviral activities when compared to the parent drugs.
Successes, failures, and future prospects of prodrugs and their clinical impact
Published in Expert Opinion on Drug Discovery, 2019
Prodrugs have been developed for the treatment of microbial and protozoal infections. Bacampicillin and pivampicillin are ester penicillin-class prodrugs. Bacampicillin is 1ʹ- ethoxycarbonyloxyethyl ester prodrug of ampicillin and possesses no antimicrobial activity. During absorption, bacampicillin is rapidly and completely hydrolysed to ampicillin. Bacampicillin produces faster and higher serum concentrations of ampicillin than non-prodrug ampicillin [56]. Similarly, pivampicillin, the pivaloyloxymethyl ester prodrug of ampicillin has a higher absorption than ampicillin, but to a lesser extent [57,58].