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Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
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Nanogel-Conjugated Reverse Transcriptase Inhibitors and Their Combinations as Novel Antiviral Agents with Increased
T H Senanayake1, S Gorantla1, E Makarov1
1Department of Pharmaceutical Sciences, College of Pharmacy, and ‡Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
Molecular Pharmaceutics
|November 14, 2015
Summary
Novel nanodrugs using cholesteryl-ε-polylysine (CEPL) nanogels improve nucleoside reverse transcriptase inhibitors (NRTIs) for HIV-1 treatment. These nanoconjugates offer extended release, reduced toxicity, and enhanced efficacy in infected cells and animal models.
Area of Science:
- Nanomedicine
- Virology
- Drug Delivery
Background:
- Nucleoside reverse transcriptase inhibitors (NRTIs) are crucial in antiretroviral therapy (ART) for managing HIV-1 infection.
- Current ART faces challenges including drug toxicity, patient compliance, and targeting viral reservoirs.
- Novel drug delivery systems are needed to enhance NRTI efficacy and reduce long-term treatment complications.
Purpose of the Study:
- To develop and characterize novel NRTI prodrugs conjugated with cholesteryl-ε-polylysine (CEPL) nanogels.
- To evaluate the efficacy, pharmacokinetics, and toxicity profile of these nanodrugs in vitro and in vivo.
- To explore the potential for reduced dosing frequency and improved patient compliance.
Main Methods:
- Synthesis of NRTI 5'-succinate derivatives (sNRTI) and their conjugation to CEPL nanogels.
- Characterization of nanogel conjugates for particle size, drug loading, and release kinetics.
- In vitro evaluation of antiviral activity in HIV-infected macrophages, determining EC90 values.
- In vivo assessment of PEGylated CEPL-sAZT efficacy in a humanized mouse model of HIV-1 infection.
Main Results:
- CEPL-sNRTI nanogels exhibited biodegradability, small particle size, and high drug loading (30% by weight).
- Nanodrugs demonstrated extended drug release, enabling potential for weekly administration and showing high therapeutic index (>1000).
- Nanodrug formulations achieved significant suppression of HIV-1 reverse transcriptase activity in infected macrophages, with lamivudine conjugate being most effective (EC90 2 μM).
- PEGylated CEPL-sAZT suppressed HIV-1 RT activity to background levels in a humanized mouse model with infrequent injections.
Conclusions:
- CEPL-based nanogels represent a promising platform for developing advanced NRTI prodrugs.
- These nanodrugs offer improved pharmacokinetic profiles, reduced toxicity, and enhanced antiviral efficacy compared to free NRTIs.
- The developed nanomedicine holds potential for more convenient and effective long-term management of HIV-1 infection.
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