Synthesis, drug release and anti-HIV activity of a series of PEGylated zidovudine conjugates

Li, Wenjun; Wu, Jingde; Zhan, Peng; Chang, Yu Chia; Pannecouque, Christophe; Clercq, Erik De; Liu, Xinyong

doi:10.1016/j.ijbiomac.2012.02.019

Cited by 18 publications

(21 citation statements)

References 32 publications

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“…7 For these reasons, AZT is often not recommended for treatment for first-line treatment of HIV. 8 Release of antiretroviral drugs from nanogels, 9 hydrogels, 10 or polymer conjugates [11][12][13][14] have all provided viable options for prolonging the circulation half-life and alleviating the cytotoxic side effects. While these systems effectively prolong the action of the antiviral released, drug release mechanisms rely on the presence of bonds that are intermediately stable to hydrolysis, such as ester linkages, to attach the drug to the polymer.…”

Section: Introductionmentioning

confidence: 99%

“…11,12 While this provides a higher therapeutic window between antiviral activity and cytotoxicity, these systems do not provide complete release and usually results in a lower efficacy against HIV infectivity. [11][12][13][14] Recently, a macromolecular prodrug anti-HIV system was devised that was capable of a rapid intracellular triggered release of an antiviral drug. In this system, the AZT drug was attached through a self-4 immolative, disulfanyl ethylcarbonate linker between the drug and a methacrylate polymer side chain.…”

Section: Introductionmentioning

confidence: 99%

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Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

et al. 2016

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In this article a library of polymeric therapeutic agents against the human immunodeficiency virus (HIV) is presented. The library of statistical copolymers of varied molar mass was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. The synthesized polymers comprise pendent hydroxyl and sulfonated side chains as well as the reverse transcriptase prodrug lamivudine (3TC) attached via a disulfide self-immolative linker. The glutathione mediated release of 3TC is demonstrated as well as the antiviral efficacy against HIV entry and polymerase activity. Although a high degree of polymer sulfonation is required for effective HIV entry inhibition, polymers with approximately ∼50% sulfonated monomer demonstrated potent kinase independent reverse transcriptase inhibition. In addition, the sulfonated polymers demonstrate activity against DNA-DNA polymerase, which suggests that these polymers may exhibit activity against a broad spectrum of viruses. In summary, the polymers described provide a triple-active arsenal against HIV with extracellular activity via entry inhibition and intracellular activity by kinase-dependent lamivudine-based and kinase-independent sulfonated polymer based inhibition. Since these sulfonated copolymers are easily formulated into gels, we envision them to be particularly suited for topical application to prevent the mucosal transmission of viruses, particularly HIV.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

et al. 2016

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“…Compound 44, mPEG750 was found to be most active (IC50 = 0.11 μmol/L against HIV-I) and least toxic (IC50 = 110 μmol/L) molecule in this series. It looks an efficient method for slow and prolonged release of AZT [55]. [56].…”

Section: Conjugation Of Azidothymidine With Polymersmentioning

confidence: 99%

Zidovudine: Structural Modifications and Their Impact on Biological Activities and Pharmacokinetic Properties

Mohsin

Ahmed

Irfan

2019

J. Chil. Chem. Soc.

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Zidovudine was the first drug approved for the treatment of Acquired Immuno Deficiency Syndrome (AIDS). Its chemical name is azidothymidine (AZT). AZT use is associated with bone marrow toxicity. Shorter half-life and inability to penetrate the blood-brain barrier are the pharmacokinetic problems of this important drug molecule. Various modifications have been carried out in the structure of AZT. These include modification of hydroxyl and azido group, thymidine ring, preparation of phosphate and phosphonate derivatives, attachment of polymers and synthesis of hybrid molecules. Some of these changes produced compounds with significantly increased activity and less toxicity. This review highlights the various structural modifications of AZT and their influence on biological activities and pharmacokinetic properties.

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“…Li et al [62] developed a series of methoxy poly(ethylene glycol)-succinyl-5′- O -zidovudine conjugates (mPEG-succinyl-zidovudine (AZT), Scheme 2), and evaluated their pharmacokinetic and antiretroviral activities in rats and MT-4 cells. The polymeric drug conjugates displayed enhanced pharmacokinetic profiles and antiretroviral activity when compared to native drug.…”

Section: Art Nanomedicinesmentioning

confidence: 99%

Development of HIV Reservoir Targeted Long Acting Nanoformulated Antiretroviral Therapies

Edagwa¹,

Zhou²,

McMillan³

et al. 2014

CMC

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Human immunodeficiency virus (HIV) infection commonly results in a myriad of comorbid conditions secondary to immune deficiency. Infection also affects broad organ system function. Although current antiretroviral therapy (ART) reduces disease morbidity and mortality through effective control of peripheral viral load, restricted infection in HIV reservoirs including gut, lymphoid and central nervous system tissues, is not eliminated. What underlies these events is, in part, poor ART penetrance into each organ across tissue barriers, viral mutation and the longevity of infected cells. We posit that one means to improve these disease outcomes is through nanotechnology. To this end, this review discusses a broad range of cutting-edge nanomedicines and nanomedicine platforms that are or can be used to improve ART delivery. Discussion points include how polymer-drug conjugates, dendrimers, micelles, liposomes, solid lipid nanoparticles and polymeric nanoparticles can be harnessed to best yield cell-based delivery systems. When completely developed, such nanomedicine platforms have the potential to clear reservoirs of viral infection.

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Synthesis, drug release and anti-HIV activity of a series of PEGylated zidovudine conjugates

Cited by 18 publications

References 32 publications

Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

Triple Activity of Lamivudine Releasing Sulfonated Polymers against HIV-1

Zidovudine: Structural Modifications and Their Impact on Biological Activities and Pharmacokinetic Properties

Development of HIV Reservoir Targeted Long Acting Nanoformulated Antiretroviral Therapies

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