Amino Acid Prodrugs: An Approach to Improve the Absorption of HIV-1 Protease Inhibitor, Lopinavir
نویسندگان
چکیده
Poor systemic concentrations of lopinavir (LPV) following oral administration occur due to high cellular efflux by P-glycoprotein (P-gp) and multidrug resistance-associated proteins (MRPs) and extensive metabolism by CYP3A4 enzymes. In this study, amino acid prodrugs of LPV were designed and investigated for their potential to circumvent efflux processes and first pass effects. Three amino acid prodrugs were synthesized by conjugating isoleucine, tryptophan and methionine to LPV. Prodrug formation was confirmed by the LCMS/MS and NMR technique. Interaction of LPV prodrugs with efflux proteins were carried out in P-gp (MDCK-MDR1) and MRP2 (MDCK-MRP2) transfected cells. Aqueous solubility studies demonstrated that prodrugs generate higher solubility relative to LPV. Prodrugs displayed higher stability under acidic conditions and degraded significantly with rise in pH. Uptake and transport data suggested that prodrugs carry significantly lower affinity towards P-gp and MRP2 relative to LPV. Moreover, prodrugs exhibited higher liver microsomal stability relative to LPV. Hence, amino acid prodrug modification might be a viable approach for enhancing LPV absorption across intestinal epithelial and brain endothelial cells which expresses high levels of P-gp and MRP2.
منابع مشابه
Peptide Prodrugs: An Approach to Enhance Oral Absorption of HIV Protease Inhibitor, Lopinavir
متن کامل
Effect of Biomolecular Conformation on Docking Simulation: A Case Study on a Potent HIV-1 Protease Inhibitor
Human immunodeficiency virus infection / acquired immunodeficiency syndrome (HIV/AIDS) is a disease pertained to the human immune system. Given its crucial role in viral replication, HIV-1 protease (HIV-1 PR) is a prime therapeutic target in AIDS therapy. In this regard, the dynamic aspects of ligand-enzyme interactions may indicate an important role of conformational variability in HIV-1 PR in...
متن کاملAppearance of a single amino acid insertion at position 33 in HIV type 1 protease under a lopinavir-containing regimen, associated with reduced protease inhibitor susceptibility.
HIV drug resistance is a multifactorial phenomenon and constitutes a major concern as it results in therapy failure. The aim of this study was to assess the impact of an amino acid insertion identified at position 33 of the protease gene, derived from samples from three patients under lopinavir therapy, on viral fitness and protease inhibitor (PI) resistance. Successive samples were available f...
متن کاملGp41 and Gag amino acids linked to HIV‐1 protease inhibitor‐based second‐line failure in HIV‐1 subtype A from Western Kenya
INTRODUCTION Failure of protease-inhibitor (PI)-based second-line antiretroviral therapy (ART) with medication adherence but no protease drug resistance mutations (DRMs) is not well understood. This study investigated the involvement of gp41 and gag as alternative mechanisms, not captured by conventional resistance testing and particularly relevant in resource-limited settings where third-line ...
متن کاملC-Terminal Propeptide of BKA has a Protease Sensitive Structure Without any Inhibitory Effect on BKA
In our previous study, we compared the two α-amylase enzymes from Bacillus sp.KR8104, BKA∆(N44) and BKA∆(N44C193) which is the secreted form of it. The results indicated that the presence of 193 amino acids propeptide in the C-terminal of BKA∆(N44) changed its enzymatic parameters like an uncompetitive inhibitor in comparison to BKA∆(N44C193). In the present study, we cloned the DNA sequence of...
متن کامل