Peptidophospholipids: Synthesis, phospholipase A2 catalyzed hydrolysis, and application to development of phospholipid prodrugs

Rosseto, Renato; Hajdu, Joseph

doi:10.1016/j.chemphyslip.2014.06.001

Cited by 9 publications

(8 citation statements)

References 27 publications

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“…In addition, evidence of correlation between PLA 2 biosynthesis and the degree of the bowel inflammation was also reported [21]. We, and others, have been advocating the use of a PL-prodrug approach to target PLA 2 in inflamed tissues [30,31,32,33,34,35,36]. PLA 2 hydrolyzes the fatty acid in the sn -2 position of the PL, thus releasing a free fatty acid and sn -1 lysophospholipid.…”

Section: Introductionmentioning

confidence: 97%

Phospholipid-Based Prodrugs for Colon-Targeted Drug Delivery: Experimental Study and In-Silico Simulations

et al. 2019

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In ulcerative colitis (UC), the inflammation is localized in the colon, and one of the successful strategies for colon-targeting drug delivery is the prodrug approach. In this work, we present a novel phospholipid (PL)-based prodrug approach, as a tool for colonic drug targeting in UC. We aim to use the phospholipase A2 (PLA2), an enzyme that is overexpressed in the inflamed colonic tissues of UC patients, as the PL-prodrug activating enzyme, to accomplish the liberation of the parent drug from the prodrug complex at the specific diseased tissue(s). Different linker lengths between the PL and the drug moiety can dictate the rate of activation by PLA2, and subsequently determine the amount of free drugs at the site of action. The feasibility of this approach was studied with newly synthesized PL-Fmoc (fluorenylmethyloxycarbonyl) conjugates, using Fmoc as a model compound for testing our hypothesis. In vitro incubation with bee venom PLA2 demonstrated that a 7-carbon linker between the PL and Fmoc has higher activation rate than a 5-carbon linker. 4-fold higher colonic expression of PLA2 was demonstrated in colonic mucosa of colitis-induced rats when compared to healthy animals, validating our hypothesis of a colitis-targeting prodrug approach. Next, a novel molecular dynamics (MD) simulation was developed for PL-based prodrugs containing clinically relevant drugs. PL-methotrexate conjugate with 6-carbon linker showed the highest extent of PLA2-mediated activation, whereas shorter linkers were activated to a lower extent. In conclusion, this work demonstrates that for carefully designed PL-drug conjugates, PLA2 overexpression in inflamed colonic tissues can be used as prodrug-activating enzyme and drug targeting strategy, including insights into the activation mechanisms in a PLA2 binding site.

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Section: Introductionmentioning

confidence: 97%

Phospholipid-Based Prodrugs for Colon-Targeted Drug Delivery: Experimental Study and In-Silico Simulations

et al. 2019

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“…Rosseto and Hajdu studied two PL conjugates containing antiviral oligopeptides at the sn‐ 2 position, replacing the naturally occurring FA (Table ). These two peptidophospholipid prodrugs were completely hydrolyzed by bee venom PLA 2 , producing the free antiviral oligopeptides, and this hydrolysis occurred at the same rate as naturally occurring PL.…”

Section: Lipidic Prodrugs As a Mean For Enhancing Oral Drug Delivery:mentioning

confidence: 99%

“…The oligopeptides structure included a methylene functional group, that was attached to the PL sn‐ 2 position; this α‐methylene group was shown to be necessary for successful PLA 2 activation, whereas other peptidophospholipids that lack this group, failed to be activated . In the context of the PL‐based prodrug, this α‐methylene group can be viewed as a linker that allows the prodrug‐enzyme binding, making the difference between “PLA 2 ‐resistant” and “PLA 2 ‐labile” design …”

Section: Lipidic Prodrugs As a Mean For Enhancing Oral Drug Delivery:mentioning

confidence: 99%

Lipidic prodrug approach for improved oral drug delivery and therapy

Marković

Ben‐Shabat

Keinan

et al. 2018

Medicinal Research Reviews

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In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s).The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed.Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.

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“…Conjugation strategy in this case usually involves hydroxyl group of the drug for linking to the phosphate group. In contrast, a different design, using the PL sn -2 position of the prodrug and taking advantage of PLA 2 -mediated prodrug activation became increasingly employed [28,29,30,35,36,37,38]. When linking the drug to the sn -2 position of the PL several synthetic techniques can be applied; a common method involves protecting the amino group of the linker, and connecting it to the sn -2 position of lysophospholipid, followed by removal of the protection and conjugation to the drug moiety.…”

Section: Phospholipid-based Prodrugs: Structures and Applicationsmentioning

confidence: 99%

“…Recently, PL conjugates of antiviral oligopeptides in the sn -2 position of the PL, were studied [38]. These PL-prodrugs were entirely hydrolyzed by bee venom PLA 2 , releasing the free oligopeptides in the same rate of reaction as physiological PL.…”

Section: Phospholipid-based Prodrugs: Structures and Applicationsmentioning

confidence: 99%

Prospects and Challenges of Phospholipid-Based Prodrugs

Markovic,

Ben-Shabat,

Keinan

et al. 2018

Pharmaceutics

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Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound to the lipid carrier, which can be triglyceride, fatty acids, steroid, or phospholipid (PL). The focus of this article is PL-based prodrugs, which includes a PL carrier covalently bound to the active drug moiety. An overview of relevant physiological lipid processing pathways and absorption barriers is provided, followed by drug delivery/therapeutic application of PL-drug conjugates, as well as computational modeling techniques, and a modern bioinformatics tool that can aid in the optimization of PL conjugates. PL-based prodrugs have increased lipophilicity comparing to the parent drug, and can therefore significantly improve the pharmacokinetic profile and overall bioavailability of the parent drug, join the endogenous lipid processing pathways and therefore accomplish drug targeting, e.g., by lymphatic transport, drug release at specific target site(s), or passing the blood-brain barrier. Moreover, an exciting gateway for treating inflammatory diseases and cancer is presented, by utilizing the PL sn-2 position in the prodrug design, aiming for PLA2-mediated activation. Overall, a PL-based prodrug approach shows great potential in improving different drug delivery/therapy aspects, and is expected to grow.

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Peptidophospholipids: Synthesis, phospholipase A2 catalyzed hydrolysis, and application to development of phospholipid prodrugs

Cited by 9 publications

References 27 publications

Phospholipid-Based Prodrugs for Colon-Targeted Drug Delivery: Experimental Study and In-Silico Simulations

Phospholipid-Based Prodrugs for Colon-Targeted Drug Delivery: Experimental Study and In-Silico Simulations

Lipidic prodrug approach for improved oral drug delivery and therapy

Prospects and Challenges of Phospholipid-Based Prodrugs

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