Background Humanized mice generate a lymphoid system of human origin subsequent to transplantation of human CD34+ cells and thus are highly susceptible to HIV infection. Here we examined the efficacy of antiretroviral treatment (ART) when added to food pellets, and of long-acting (LA) antiretroviral compounds, either as monotherapy or in combination. These studies shall be inspiring for establishing a gold standard of ART, which is easy to administer and well supported by the mice, and for subsequent studies such as latency. Furthermore, they should disclose whether viral breakthrough and emergence of resistance occurs similar as in HIV-infected patients when ART is insufficient. Methods/Principal Findings NOD/shi-scid/γ c null (NOG) mice were used in all experimentations. We first performed pharmacokinetic studies of the drugs used, either added to food pellets (AZT, TDF, 3TC, RTV) or in a LA formulation that permitted once weekly subcutaneous administration (TMC278: non-nucleoside reverse transcriptase inhibitor, TMC181: protease inhibitor). A combination of 3TC, TDF and TMC278-LA or 3TC, TDF, TMC278-LA and TMC181-LA suppressed the viral load to undetectable levels in 15/19 (79%) and 14/14 (100%) mice, respectively. In successfully treated mice, subsequent monotherapy with TMC278-LA resulted in viral breakthrough; in contrast, the two LA compounds together prevented viral breakthrough. Resistance mutations matched the mutations most commonly observed in HIV patients failing therapy. Importantly, viral rebound after interruption of ART, presence of HIV DNA in successfully treated mice and in vitro reactivation of early HIV transcripts point to an existing latent HIV reservoir. Conclusions/Significance This report is a unique description of multiple aspects of HIV infection in humanized mice that comprised efficacy testing of various treatment regimens, including LA compounds, resistance mutation analysis as well as viral rebound after treatment interruption. Humanized mice will be highly valuable for exploring the antiviral potency of new compounds or compounds targeting the latent HIV reservoir.
Trypanothione is the key molecule in the defence mechanism of Trypanosoma and Leishmania against oxidative stress. The uniqueness of trypanothione makes the metabolism of this molecule an attractive target in antitrypanosomal and antileishmanial drug design. It became clear that this antioxidant cascade can be considered as the "Achilles heel" of these parasites. The following targets and their respective inhibitors will be discussed: biosynthesis of trypanothione with glutathionylspermidine synthetase and trypanothione synthetase; biosynthesis of glutathione with gamma-glutamylcysteine synthetase; biosynthesis of spermidine with ornithine decarboxylase; trypanothione hydroperoxide metabolism with tryparedoxine peroxidase, tryparedoxine and trypanothione reductase.
Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl-hydroxy-aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC(50) value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC(50) of 270 nM against HIV-1 in a cell-based assay.
HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.
In view of the increasing interest in injectable controlled release formulations for the treatment of chronic diseases, injectable polymeric microspheres consisting of a surface layer of poly(lactic-co-glycolic acid) (PLGA) and an underlying polyvinylpyrrolidone (PVP) layer were previously developed. The present study focuses on the influence of heat and humidity on the surface characteristics of these spray-dried PLGA/PVP microspheres. The response of the polymeric matrix to these factors will provide an insight into the expected release behavior and stability of the formulation. This should result in the development of a drug matrix with desired and tunable characteristics in terms of physicochemical stability and drug release profile, relevant in a later stage of research. Glass transition temperatures (Tgs) and miscibility behavior were analyzed by modulated differential scanning calorimetry (MDSC). Scanning electron microscopy (SEM) provided insight in particle morphology. Atomic force microscopy (AFM) was used to study the nanoscale topography and phase behavior of the samples. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) were utilized for surface chemical analysis and quantification respectively. It could be concluded that the surface characteristics (chemical composition, phase behavior, and topography) of spray-dried PVP/PLGA microparticles were affected by exposure to heat and humidity. When exposed to these conditions, a surface rearrangement occurs whereby an increase of PVP at the surface is observed, coupled with a decrease in PLGA. This phenomenon can be explained based upon the relative thermal characteristics and consequent molecular mobility of the two polymers.
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