anti-HIV Replication Research Articles

The Effect of Vitamin D on Anti-HIV microRNAs and HIV Replication in Vitro Model

The active form of vitamin D, 1α,25-Dihydroxyvitamin D3, induced proteins expression that associated with anti-HIV activity. Moreover, several studies have reported that some microRNAs inhibit HIV replication by targeting 3' LTR HIV mRNAs designated anti-HIV microRNAs. To date, the effect of 1α,25-Dihydroxyvitamin D3 (1,25(OH)2D3) on anti-HIV microRNAs expression is unknown. We aimed to determine whether 1,25(OH)2D3 effects of anti-HIV microRNAs expression and inhibit of HIV replication. microRNAs expression were analyzed by stem-loop RT-PCR in jurkat cell line and PBMC culture system. HIV production was examined by ELISA method. Our results show that 1,25(OH)2D3 no effect on anti-HIV microRNAs expression in both jurkat cell line and PBMC culture system. Moreover, CD4 T cells could not be reduce HIV-1 production which treated by 1,25(OH)2D3. All these data may contribute to the mechanism of 1,25(OH)2D3 on virus infection.

Synthesis and Structure-Activity Relationship Correlations of Gnidimacrin Derivatives as Potent HIV-1 Inhibitors and HIV Latency Reversing Agents.

Currently, due to the HIV latency mechanism, the search continues for effective drugs to combat this issue and provide a cure for AIDS. Gnidimacrin activates latent HIV-1 replication and inhibits HIV-1 infection at picomolar concentrations. This natural diterpene was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells. Therefore, gnidimacrin is an excellent lead compound, and its anti-HIV potential merits further investigation. Twenty-nine modified gnidimacrin derivatives were synthesized and evaluated in assays for HIV replication and latency activation to establish which molecular structures must be maintained and which can tolerate changes that may be needed for better pharmacological properties. The results indicated that hydroxyl substituents at C-5 and C-20 are essential, while derivatives modified at 3-OH with aromatic esters retain anti-HIV replication and latent activation activities. The half-lives of the potent GM derivatives are over 20 h, which implies that they are stable in the plasm even though they contain ester linkages. The established structure-activity relationship should be useful in the development of gnidimacrin or structurally related compounds as clinical trial candidates.

Correction to: Voltammetric detection of anti-HIV replication drug based on novel nanocomposite gold-nanoparticle-CaCO3 hybrid material.

The Figs.2, 4 and 5 were published wrongly in this paper, due to inadvertent compilation of figures during uploading the paper.

Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity.

Several fluorinated derivatives of the anti-HIV maturation agent bevirimat (1) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid (2) skeleton or in the attached side chains. Compound 18, which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1NL4-3. In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2-related compounds.

Electrochemical impediometric detection of anti-HIV drug taking gold nanorods as a sensing interface

In present work, gold nanorods were used for amplification of electrochemical sensing of anti-HIV replication drug i.e. deferiprone. Gold nanorods (nano Au) deposited onto pencil graphite electrode (PGE) has been utilized for covalent immobilization of horse radish peroxidase (HRP), via glutaraldehyde (Glu), for deferiprone detection using impedimetric technique. Gold nanorods (nano Au) prepared were characterized by TEM and XRD. The resulting nano Au sensor exhibited a good response to deferiprone with a wide linear range (0.005–1000µM) and a low detection limit 0.005µM. The biosensor also showed a short response time (within 15s). In addition, the biosensor exhibited high reproducibility, good storage stability and anti-interference ability. The applicability of the nano Au sensor is to determine deferiprone level in spiked urine and serum samples.

Voltammetric detection of anti-HIV replication drug based on novel nanocomposite gold-nanoparticle-CaCO3 hybrid material.

A novel bionanocomposite, horse radish peroxidase- gold-nanoparticle-Calcium carbonate (HRP-AuNPs-CaCO3), hybrid material was encapsulated by silica sol on a glassy carbon electrode (GCE). The fabricated modified electrode was used as a novel voltammetric sensor for electrochemical sensing of anti-HIV replication drug i.e. deferiprone. The surface morphology of the modified electrode was characterized by scanning electron microscopy (SEM). Results obtained from the voltammetric measurements show that HRP-AuNPs-CaCO3 modified GCE offers a selective and sensitive electrochemical sensor for the determination of deferiprone. Under experimental conditions, the proposed voltammetric sensor has a linear response range from 0.01 to 10,000μM with a detection limit of 0.01μM. Furthermore, the fabricated sensor was successfully applied to determine deferiprone level in spiked urine and serum samples.

Anti-AIDS Agents 90. Novel C-28 Modified Bevirimat Analogues as Potent HIV Maturation Inhibitors

In a continuing study of bevirimat (2), the anti-HIV-maturation clinical trials agent, 28 new betulinic acid (BA, 1) derivatives were designed and synthesized. Among these compounds, 17, with a C-28 MEM ester moiety, and 22, with a C-28 ethyl hexanoate, increased the anti-HIV replication activity compared with 2 by 2-fold while compounds 40, 41, 48, and 49, with C-28 piperazine or piperidine amide substitutions, increased the activity by 3- to 15-fold. The best new compound, 41, exhibited an anti-HIV IC(50) of 0.0059 μM compared with 0.087 μM for 2. All of the active compounds showed only antimaturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the antimaturation activity of 2 without any antientry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates.

Electrochemistry of deferiprone as an orally active iron chelator and HIV-1 replication inhibitor and its determination

The electrochemical behavior of the anti-thalassemia and anti-HIV replication drug, deferiprone, was investigated by cyclic voltammetry (CV) at a platinum electrode. In an acetate buffer solution, pH = 4.0, two irreversible anodic peaks for deferiprone, with E(0)1 = 875 mV and E(0)2 = 1235 mV (vs. Ag/AgCl) appeared at a potential sweep rate of 50 mV s-1. Cyclic voltammetric study indicated that the oxidation process is irreversible and diffusion-controlled. The diffusion and the electron transfer coefficients of deferiprone were found to be 3.50 × 10-6 cm² s-1 and 0.57, respectively. A sensitive, simple and time-saving differential pulse voltammetric procedure was developed. Using our proposed method, deferiprone can be determined with a detection limit of 1.43 × 10-5 mol L-1. The applicability of the method to direct assays of spiked human serum and urine fluids, and to commercial tablets, is described.

Electrocatalytic oxidation of deferiprone and its determination on a carbon nanotube-modified glassy carbon electrode

The electrochemical behavior of the anti-thalassemia and anti-HIV replication drug, deferiprone, was investigated on a carbon nanotube-modified glassy carbon (GC-CNT) electrode in phosphate buffer solution, pH 7.40 (PBS). During oxidation of deferiprone, two irreversible anodic peaks, with E 1 0 = 452 and E 2 0 = 906 mV , appeared, using GC-CNT. Cyclic voltammetric study indicated that the oxidation process is irreversible and diffusion controlled. The number of exchanged electrons in the electro-oxidation process was obtained, and the data indicated that deferiprone is oxidized via two two-electron steps. The results revealed that carbon nanotube (CNT) promotes the rate of oxidation by increasing the peak current, so that deferiprone is oxidized at lower potentials, which thermodynamically is more favorable. This result was confirmed by impedance measurements. The diffusion coefficient, electron-transfer coefficient and heterogeneous electron-transfer rate constant of deferiprone were found to be 1.49 × 10 −6 cm 2 s −1, 0.44, and 3.83 × 10 −3 cm s −1, respectively. A sensitive, simple and time-saving differential-pulse voltammetric procedure was developed for the analysis of deferiprone. Using the proposed method, deferiprone can be determined with a detection limit of 5.25 × 10 −7 M. The applicability of the method to direct assays of spiked human serum and urine fluids is described.

Synthesis and anti-HIV evaluation of the novel 2-(m-chlorobenzyl)-4-substituted-7-methyl-1, 1, 3-trioxo-pyrazolo[4, 5-e] [1, 2, 4]thiadiazines

A novel series of 2-(m-Chlorobenzyl)-4-substituted-1, 1, 3-trioxo-2H, 4H-pyrazolo[4, 5-e][1, 2, 4] thiadiazines (7a-k) were synthesized, and evaluated for their anti-HIV replication in MT-4 cell cultures. Compound (7a) showed activity against HIV-1-induced cytopathicity, with an EC50 value of 45.6 microM, but none of the compounds exhibited inhibitory activity against HIV-2.

Effects of CAPE-like compounds on HIV replication in vitro and modulation of cytokines in vivo

Five CAPE-like compounds, namely caffeic acid phenethyl ester (CAPE), methyl caffeate (MC), ethyl 3-(3,4-dihydroxyphenyl)acrylate (EC), phenethyl dimethyl caffeate (PEDMC) and phenethyl 3-(4-bromophenyl)acrylic (BrCAPE) were tested for their anti-HIV replication in vitro and immune modulation effects in vivo. Short-term cytotoxicity was assessed by Trypan Blue stain and MTT assay. For antiviral assays, M-tropic (strain JRCSF), T-tropic (strain NL-4-3) and dual tropic (strain 89.6) HIV isolates were used in peripheral blood mononuclear cell (PBMC) culture. None of these CAPE-like compounds showed significant cytotoxicity in the treatment of PBMCs. By P24 EIA tests, CAPE, MC and EC significantly inhibited HIV replication in PBMC cells, but PEDMC and BrCAPE showed only slightly inhibitory effects. The in vivo modulatory effects on six cytokines [interleukin (IL)-2, IL-4, IL-6, interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF) and soluble Fas] were analysed. BALB/c mice treated with different doses or not treated with these CAPE-like chemicals showed that cytokines were increased to different extents by the different treatments. However, the concentrations of IL-6 and GM-CSF were not significantly affected by administration of any of these compounds (P > 0.05). The different effects of treatments on anti-HIV replication and cytokine modulation suggested that these compounds affect virological and immunological response via different mechanisms. The virological and immunological mechanisms and response to these treatments need to be elaborated in further studies in order to derive the structural features of more effective compounds. Since neither death nor pathological change in the mice were observed in this study, these CAPE-like compounds are worth studying further as potential chemotherapy agents for anti-HIV infection and cytokine modulation.

RNase S complex bearing arginine-rich peptide and anti-HIV activity.

Basic peptide-mediated protein delivery into living cells is becoming recognized as a potent approach for the understanding of cellular mechanisms and drug delivery. We have prepared the conjugates of the S-peptide (1-15) derived from RNase S with membrane-permeable basic peptides, octaarginine and the human immunodeficient virus (HIV)-1 Rev (34-50). The RNase S complexes, formed among these S-peptide (1-15)-basic peptide conjugates and the S-protein and having a dissociation constant in the range of 10(-5) M, efficiently penetrated into the HeLa cells. These RNase S complexes exerted an anti-HIV replication activity. The time-of-drug-addition assay suggested that the site of action for these complexes would reside in the stages between the viral entry into the cells and reverse transcription. The present study exemplified the applicability of the arginine-rich peptides to the intracellular targeting of non-covalent protein complexes and supramolecular assemblies for the research in chemical and cellular biology.

Antitumour and anti-AIDS triterpenes from Celastrus hindsii

Four new triterpene compounds, celasdin-A, celasdin-C, anti-AIDS celasdin-B and cytotoxic maytenfolone-A, were isolated from Celastrus hindsii. The structural determination of maytenfolone-A, celasdin-A, celasdin-B and celasdin-C, as well as the structure-activity relationships of these new compounds and derivatives, are discussed. Maytenfolone-A was further confirmed by X-ray studies. Biological evaluation showed that Maytenfolone-A demonstrated cytotoxicity against hepatoma (HEPA-2B, ED 50 = 2.3 μg ml −1) and nasopharynx carcinoma (KB, ED 50 = 3.8 μg ml −1). Celasdin-B was found to exhibit anti-HIV replication activity in H9 lymphocyte cells with an EC 50 of 0.8 μg ml −1.

Synthesis and anti-HIV activity of dibenzylbutyrolactone lignans

Five optically active dibenzylbutyrolactone lignans were synthesized through a lipase-catalyzed transesterification route, and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells. Compounds 1 and 2 demonstrated anti-HIV replication activity with an EC 50 values of 2.2 and 0.16 μg/ml and a therapeutic index values of 9.1 and 5, respectively. Structure-antiviral activity relationships are discussed.

Anti-AIDS agents—XIX. Neotripterifordin, a novel anti-HIV principle from Tripterygium wilfordii: Isolation and structural elucidation

A new kaurane type diterpene lactone, neotripterifordin (1), has been isolated from the roots of Tripterygium wilfordii. The structure of 1 was elucidated by spectroscopic methods, which included the concerted application of a number of 2-D NMR techniques including 1H- 1H COSY, phase-sensitive NOESY, HETCOR, and long-range HETCOR. Compound 1 showed potent anti-HIV replication activity in H9 lymphocyte cells with an EC 50 of 25 nM and TI of 125.

Renal disposition and drug interaction screening of (-)-2'-deoxy-3'-thiacytidine (3TC) in the isolated perfused rat kidney.

Dideoxynucleoside bases are used for the treatment of acquired immune deficiency syndrome (AIDS), acting by inhibiting reverse transcriptase and preventing human immunodeficiency virus (HIV) replication. Currently, AZT (zidovudine), ddC (zalcitibine), and ddI (didanosine) are available to the medical community to prevent the onset of AIDS in HIV-infected individuals. 3TC (-)-2'-deoxy-3'-thiacytidine, lamivudine), a new dideoxynucleoside base, is currently undergoing Phase II/III trials, and has exhibited anti-HIV replication activity, a favorable adverse event safety profile, and is eliminated via renal mechanisms. Concomitantly administered drugs could potentiate the effects of 3TC due to interaction in the kidney. An isolated perfused rat kidney (IPK) technique was used to screen several clinically relevant drugs for potential interaction with 3TC. The following perfusions were performed: baseline 3TC; and 500 ng/mL 3TC with clinically relevant concentrations of AZT, ddC, ddI, probenecid, trimethoprim, sulfamethoxazole, ranitidine, and cimetidine. Renal clearance of 3TC was nonlinear between 500 and 5000 ng/mL, decreasing from 3.06 to 1.74 mL/min. Excretion ratio also decreased, from 3.67 (500 ng/mL) to 2.49 (5000 ng/mL), consistent with a decrease in 3TC secretion. AZT, ddI, and ddC elicited no or minimal effects on 3TC elimination at the concentrations studied. However, trimethoprim caused significant reductions in 3TC elimination parameters: clearance and excretion ratio decreased to 1.25 mL/min and 1.43, respectively. These results indicate that caution should be exercised when the combination of 3TC and trimethoprim are administered to AIDS patients.

Anti-AIDS agents, 4. Tripterifordin, a novel anti-HIV principle from Tripterygium wilfordii: isolation and structural elucidation.

A new kaurane-type diterpene lactone, tripterifordin [1], has been isolated from the roots of Tripterygium wilfordii. The structure of 1 was elucidated by spectroscopic methods, including the concerted application of a number of 2D nmr techniques that involved the 1H-1H COSY, heteronucleus-detected variants of the heteronuclear chemical shift correlation (HETCOR), phase-sensitive NOESY, and long-range HETCOR. Compound 1 shows anti-HIV replication activity in H9 lymphocyte cells with an EC50 of 1 microgram/ml.