ABSTRACT
The pace of discovery of new antiretroviral (ARV) drugs has slowed, although the efficacy and safety of once-daily fixed dose combinations have been extensively investigated. Several traditional ARV drugs remain in phase III clinical trials. This review summarizes current information on ARV drugs in phase III clinical trials and focuses on the development of ARV drugs in the next decade.
ABSTRACT
Unlike human immunodeficiency virus (HIV) and hepatitis B virus (HBV), hepatitis C virus (HCV) infection is a curable disease. Current direct antiviral agent (DAA) targets are focused on HCV NS3/4A protein (protease), NS5B protein (polymerase) and NS5A protein. The first generation of DAAs includes boceprevir and telaprevir, which are protease inhibitors and were approved for clinical use in 2011. The cure rate for genotype 1 patients increased from 45% to 70% when boceprevir or telaprevir was added to standard PEG-IFN/ribavirin. More effective and less toxic second generation DAAs supplanted these drugs by 2013. The second generation of DAAs includes sofosbuvir (Sovaldi), simeprevir (Olysio), and fixed combination medicines Harvoni and Viekira Pak. These drugs increase cure rates to over 90% without the need for interferon and effectively treat all HCV genotypes. With these drugs the "cure HCV" goal has become a reality. Concerns remain about drug resistance mutations and the high cost of these drugs. The investigation of new HCV drugs is progressing rapidly; fixed dose combination medicines in phase III clinical trials include Viekirax, asunaprevir+daclatasvir+beclabuvir, grazoprevir+elbasvir and others.
ABSTRACT
Besides 36 (28 single-tablets and 8 fixed-dose combinations) used antiretroviral drugs clinically, there are a number of investigational antiretroviral agents currently in phase 2-3 clinical trial. Tenofoviralafenamidefumarate (TAF) is a novel nucleoside analogue reverse transcriptase inhibitor that is potent and less toxicity than tenofovir (TDF). Doravirine is a non-nucleoside analogue reverse transcriptase inhibitor that demonstrates activity against NNRTI-resistant viral strains. GSK744 is an integrase inhibitor with a long acting preparation. In addition, several drugs with new mechanisms are also noted, for example, BMS-663 068 is a small molecule CD4 attachment inhibitors and cenicriviroc is a novel CCR5/CCR2 antagonist with antiretroviral activity and anti-inflammatory effects. Several drug classes that target known pathways in HIV latency have being developed, and leading the list are histone deacetylase inhibitors. Other agents include protein kinase C activators, positive transcription elongation factor activators, DNA methyl-transferase inhibitors and histone methyl-transferase inhibitors and so on. This review is focused on the above-mentioned drug candidates that may be used in clinical in next couple of years and those compounds that can reverse latent HIV infections.
ABSTRACT
The purpose of this study is to find out anti-HIV-1 reverse transcriptase (RT)/protease (PR) activity and inhibition of virus replication in cell cultures of novel coumarin analogs and determine their structure-activity relationship. Coumarin derivatives have been demonstrated to inhibit the activity of HIV-1 RT/PR in cell free system. It also shows inhibition effects to HIV-1 replication in cell culture. Based on the Chinese traditional pharmacological characteristics and protein three dimension computer aided design, analogs of tetracyclic dipyranocoumarin were synthesized from natural leading compounds. We studied the relationship of antiviral effects and chemical structures via HIV-1 PR/RT enzyme models and cell culture model system. Seven compounds were designed and tested. Several compounds showed anti-HIV-1 activity in varying degrees, especially V0201 showed much higher anti-HIV-1 activity with 3.56 and 0.78 micromol x L(-1) of IC50 against HIV-1 PR/RT and 0.036 micromol x L(-1) against HIV-1 replication in PBMC cultures. V0201 with a novel structure may be a new leading compound. These new compounds are valuable for development of new anti-HIV drugs in the future.
ABSTRACT
Resveratrol, isorhapontigenin and pinosylvin, isolated from Gnetum parvifolium, and their analogues have been synthesized and tested for their inhibitory activity of HIV-1. Natural product 12a and analogues (12d, 12e, 12g) display significant inhibitory activity of HIV-1 replication. Among them, compound 12d (trans-3, 4, 5, 4'-tetrahydroxystilbene) exhibits the most potent anti-HIV-1 activity with an IC50 value of 1.84 micromol x L(-1).
ABSTRACT
In the two decades since AZT was first approved for clinical use in 1987, 24 additional antiretroviral agents have been approved. They include 7 nucleoside analogs, a nucleotide analog and 4 non-nucleoside reverse transcriptase inhibitors, 10 protease inhibitors, 2 entry inhibitors and an integrase inhibitor. More than 20 investigational agents are currently being studied in clinical trials. Highly active antiretroviral therapy (HAART), which involves a combination of anti-HIV-1 drugs, is extremely effective in suppressing HIV-1 replication and increasing CD4+ number and results in substantial reductions in HIV-1-related morbidity and mortality. In last 20 years, much has been learned about resistance to antiretroviral drugs, drug interactions and metabolic complications of antiviral drug use. Drugs are now selected on the basis of resistance tests and on the risk of specific drug complications in individual patients. As a result, decisions about the therapy of HIV/AIDS have become personalized and are made on a patient-by-patient basis. With appropriate medical management, a person with HIV-1 now has the possibility of a nearly normal life expectancy.
ABSTRACT
An improved and practical synthesis of racemic 11-demethylcalanolide A [(±)-1] was developed. This improved process involved Pechmann reaction on phloroglucinol with ethyl butyrylacetate to give 5, 7,-dihydroxy-4-n-propylcoumarin(3). Poly phosphoric acid (PPA) catalyzed acylation of compound(3) with crotonic acid, then intramolecular cyclization was achieved simultaneously in one step to afford the key intermediate chromanone(4). A microwave assisted synthetic method preparing chromene(6) using chromenynation of chromanone(4) with 1, 1-diethoxy-methyl-2-butene was conducted. Luche reduction of chromene(6) using NaBH<,4> with CeCl3·7H2O preferably gave (±)-1. The overall yield of this four step synthesis of (±)-1 was around 32% increasing one fold more than that of the previous method. An in vitro investigation showed that (±)-1 exhibited inhibitory activities against both wild-type and drug-resistant HIV-1 in HIV-1 RT and cell culture assay, and significant synergistic effects in combination with AZT, T-20, and indinavir. Its LD50 of acute toxicity in mice by intragastric administration and by intraperitoneal injection were 735.65mg·kg-1 and 525.10mg·kg-1, respectively. The C<,max> and AUC<,0-∞> were 0.54μg·mL-1 and 1.08(μg·mL-1)·h, respectively. The dynamics study of the inhibition of mice sera on HIV-1 RT showed that mice treated with 100mg·kg-1 (±)-1 once intraperitoneally were similar to that of 5mg·kg-1 of known clinical effective anti-HIV-1 drug neverapine. The results suggested that further investigation of the anti-HIV candidate (±)-1 was warranted.
ABSTRACT
Objective To study the activity of Wuweilingqi capsule alone and the synergy with other anti-HIV-1 inhibitors against various HIV-1 isolates,and investigate its immunological impacts for CD4+ and CD8+ T cells. Method Wuweilingqi capsule was extracted from a traditional Chinese medicine recipe which contains 5 herbs,it showed anti-retroviral activity in vitro in the cultures of human peripheral blood mononuclear cells (PBMC) and T cell lines (H9 and MT2). Results Wuweilingqi capsule inhibited HIV-1018a (an AZT-sensitive clinical isolate) in PBMC and HTLV-ⅢB (a HIV-1 lab isolate) in H9 and MT-2 T cell lines markedly,and the therapeutic indexes (TI) were 96,84 and 181 separately,but weakly inhibitory activity against HIV-1018c (an AZT-resistant clinical isolate) and chronically infective HTLV-ⅢB were demonstrated. Significant synergy against HIV-1018a and HIV-1018c replication between Wuweilingqi capsule and AZT,indinavir or T-20 were observed. In addition,Wuweilingqi capsule significantly increased PBMC proliferation,interferon-gamma secreting cell number with or without a stimulation of PHA or candida. Conclusion Although Wuweilingqi capsule did not show so strong anti-HIV-1 activity as known west drugs in clinical,its good synergy and significant increase of immune activity suggests that it will be an available and characteristic agent against HIV-1 replication.
ABSTRACT
Objectives:To study the effects of gene therapy with tissue type plasminogen activator(t PA)cDNA on the formation of thrombo embolism in vascular anastomotic sites. Methods:①The cDNA encoding t PA was amplified by RT PCR using the isolated total RNA as the template from the Bowes melanoma cells.②Recombinant plasmid pAdCMV t PA was cotransfected into 293 cells with pJMa 17 ,and the infectious but replication deficient AdCMV t PA was generated.③The rats were randomly divided into the control and treatment groups.11 0 nylone medical suture was applied to perform rat carotid artery end to end anastomoses.In the treatment group,AdCMV t PA solution was injected into the vascular anastomotic site while AdCMV (no containing t PA DNA) solution was injected into the control group. By means of RT PCR and chromogenic plasmin substrates,the following results were obtained. Results:①The t PA cDNA was successfully cloned and its eukaryotic expressing vector was constructed.②When the isolated RNA was performed with RT PCR,1.69 kb band appeared in the treatment group while the band could not be found in the control group.The t PA activity could be detected postoperatively on the 1st,2 nd,3 rd,4 th,5 th,6 th,7 th,10 th and 13 th day of the treatment,but could not be detected in the control group. Conclusions:The t PA gene can produce t PA having biological activity at anastomotic sites, possibly prevent the formation of thrombus embolism effectively and develop the anastomotic patency.