Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased Efficacy against HIV-1 Infection

Abstract

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) are an integral part of the current anti-retroviral therapy (ART), which dramatically reduced the mortality from AIDS and turned the disease from lethal to chronic. The further steps in curing the HIV-1 infection must include more effective targeting of infected cells and virus sanctuaries inside the body and modification of drugs and treatment schedules to reduce common complications of the long-term treatment and increase patient compliancy. Here, we describe novel NRTI prodrugs synthesized from cholesteryl-ε-polylysine (CEPL) nanogels by conjugation with NRTI 5′-succinate derivatives (sNRTI). Biodegradability, small particle size and high NRTI loading (30% by weight) of these conjugates; extended drug release, which would allow a weekly administration schedule; high therapeutic index (>1000) with a lower toxicity compared to NRTIs; and efficient accumulation in macrophages known as carriers for HIV-1 infection are among the most attractive properties of new nanodrugs. Nanogel conjugates of Zidovudine (AZT), Lamivudine (3TC) and Abacavir (ABC) have been investigated individually and in formulations similar to clinical NRTI cocktails. Nanodrug formulations demonstrated 10-fold suppression of reverse transcriptase activity (EC90) in HIV-infected macrophages at 2–10, 2–4 and 1–2 μM drug levels, respectively for single nanodrugs, dual and triple nanodrug cocktails. Nanogel conjugate of Lamivudine was the most effective single nanodrug (EC90 2 μM). Nanodrugs showed a more favorable pharmacokinetics compared to free NRTIs. Spared i.v. injections of PEGylated CEPL-sAZT alone could efficiently suppress HIV-1 RT activity to background level in humanized mouse (hu-PBL) HIV model.

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

“…Compound 46 presented good pharmacokinetic properties, less toxicity and tenfold suppression of reverse transcriptase activity. The CEPL-nucleoside reverse transcriptase inhibitor (NRTI) prodrug released the nucleoside at a sustained rate and was found to be an efficient drug carrier [57].…”

Nanoformulated Antiretrovirals for Penetration of the Central Nervous System: State of the Art

“…NRTIs are a widely differentiated class, in which 3TC, emtricitabine (FTC), ABC and TDF are not associated to neurologic adverse events. Moreover, such drugs have proven to be the most effective backbone on sensitive HIV-1 strains and very active on brain macrophages (Senanayake et al 2015 ). Protease inhibitors, the class that revolutioned the antiretroviral therapy, today appear weaker in comparison to some NNRTIs (Bonora et al 2009 ) and to INSTIs (Molina et al 2015 ).…”

Nanomedicines for Malaria Chemotherapy: Encapsulation vs. Polymer Therapeutics

“…in Infectious DiseasesTo the best of our knowledge and research, no polymer-drug conjugates for the major infectious diseases, malaria and tuberculosis, are currently in any stage of pre-clinical or clinical trials. Most of the research on the application of this technology to infectious diseases has focussed on anti-retroviral drugs(179)(180)(181)(182)(183). The anti-retroviral drug saquinavir was conjugated to PEG(184).…”