No abstract available.
Dideoxynucleosides ; Anti-HIV Agents ; Reverse Transcriptase Inhibitors

Both reverse transcriptase (RT) and integrase (IN) play crucial roles in the life cycle of HIV-1, which are also key targets in the area of anti-HIV drug research. Reverse transcriptase inhibitors are involved in the most employed drugs used to treat AIDS patients and HIV-infected people, while one of the integrase inhibitors has already been approved by US FDA to appear on the market. Great achievement has been made in the research on both, separately. Recently, much more attention of medicinal chemistry researchers has been attracted to the strategies of multi-target drugs. Compounds with excellent potency against both HIV RT and IN, evidently defined as dual inhibitors targeting both enzymes, have been obtained through considerable significant exploration, which can be classified into two categories according to different strategies. Combinatorial chemistry approach together with high throughput screening methods and multi-target-based virtual screening strategy have been useful tools for identifying selective anti-HIV compounds for long times; Rational drug design based on pharmacophore combination has also led to remarkable results. In this paper, latest progress of both categories in the discovery and structural modification will be covered, with a view to contribute to the career of anti-HIV research.
Drug Design ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; HIV Reverse Transcriptase ; antagonists & inhibitors ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Reverse Transcriptase Inhibitors ; chemistry ; pharmacology ; Structure-Activity Relationship

For 16 years after the finding of HIV as an agent of AIDS in 1981, HIV therapeutic drugs of reverse transcriptase inhibitors (AZT, ddI, ddC, d4T) and protease inhibitors have been developed. Recent studies also were focused on a combination therapy by using HIV therapeutic drugs or natural compounds. Korean red ginseng (KRG) of natural compounds has been well known as a good reinforcement agent in Asia. The percentage of CD3+CD4+ T cell in nine HIV-infected patients without KRG treatment averaged 17.8% on baseline and decreased 15.8% after 6 months, whereas the percentage of the cell in fifteen HIV-infected patients with KRG treatment averaged 15.3% on baseline and increased up to 18.9% after the same period. The average percentage of CD3+CD8+ T cell of KRG-nontreated and KRG-treated HIV patients increased after 6 months 47.8% to 50.7% and 44.7% to 51.4%, respectively; and the average percentage of B and NK cell in the KRG-nontreated and KRG-treated HIV patients decreased 9.4% to 7.9% and 13.0% to 9.7%, 8.9% to 8.5% and 16.2% to 11.6%, respectively, KRG, therefore, didn't have any effects on the CD3+CD8+ T cell, B cell, and NK cell. However, it seems that KRG has a potential activity for stimulating the
Asia ; HIV ; Humans ; Killer Cells, Natural ; Lymphocyte Subsets* ; Lymphocytes* ; Panax* ; Protease Inhibitors ; Reverse Transcriptase Inhibitors

The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively. Studies GS-US-236-115 and GS-US-236-121 were randomized, open-label, 96-week long conducted in ART-experienced subjects, who switched to E/C/F/TDF from ritonavir-boosted protease inhibitors (PI+RTV)+F/TDF, or non-nucleoside reverse transcriptase inhibitors (NNRTI)+F/TDF regimens. The E/C/F/TDF appeared to have sustained efficacy and safety and was well tolerated in the small number of ART-naïve and ART-experienced Asian subjects.
Asian Continental Ancestry Group* ; Atazanavir Sulfate ; HIV* ; HIV-1* ; Humans ; Humans* ; Protease Inhibitors ; Reverse Transcriptase Inhibitors

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) play an important roles in the prevention and treatment of AIDS. NNRTIs can specifically target at HIV reverse transcriptase (RT) and have the advantages of high potency and low toxicity, which make them a research focus for a long time. In the guidance of structural optimization strategies (bioisosterism, molecular hybridization and scaffold hopping) in medicinal chemistry, structural modification to lead compounds can be carried out to design new compounds with different levels, which will improve the efficiency of drug discovery and decrease the cost of drug development. It is an effective way to find new NNRTIs. In this review, we will expatiate on the application of different levels of structural optimization strategies in the NNRTIs structural modification with concrete examples.
Anti-HIV Agents ; chemical synthesis ; chemistry ; Drug Design ; HIV Reverse Transcriptase ; antagonists & inhibitors ; chemistry ; Molecular Structure ; Reverse Transcriptase Inhibitors ; chemical synthesis ; chemistry

AIMSynthesis of 1-(3-phthalimido-2-oxobutyl)-4-substituted- phenylpiperazines (5-15).

METHODSThe starting material nitrogen mustard hydrochloride (16), reacted with the corresponding substituted anilines to afford piperazine hydrochlorides (17-27), which were then coupled with 1-bromo-3-phthalimidobutan-2-one (4) to give the target compounds.

RESULTSEleven target compounds (5-15) were synthesized, which were characterized by 1HNMR, IR and elemental analysis.

CONCLUSIONAnti-HIV-1 RT using HIV reverse transcriptase P-66 protein test showed that compounds 11, 14, 10 and 13 possessed inhibitory effects against HIV-1 reverse transcriptase (RT), with IC50 29.80, 35.20, 43.77 and 63.76 mumol.L-1, respectively.

HIV Reverse Transcriptase ; antagonists & inhibitors ; metabolism ; Inhibitory Concentration 50 ; Molecular Structure ; Piperazines ; chemical synthesis ; chemistry ; pharmacology ; Reverse Transcriptase Inhibitors ; chemistry ; pharmacology

JB25 and JB26 are new HIV-1 nonnucleoside reverse transcriptase inhibitors, and show potent anti-HIV activities. Sequential passage experiments with wild-type virus were performed to select and identify mutations induced by these two compounds in vitro. For the initial passage, compounds were present at approximately 2-fold IC50 in MT-2 cells. When cytopathic effect (CPE) was observed in more than 75% of the cells, the culture supernatants were collected. For the subsequent passages, fresh MT-2 cells were infected with 1 mL supernatants from the previous passage (regardless of the virus titer) and cultured in the presence of the compounds at concentrations that were increased 2-fold compared with that in the previous passage. This procedure was repeated with increasing concentrations for 12 passages. JB25 had amino acid substitution L100I (TTA-->ATA) at passage 6, and then changed into 100 M (ATA-->ATG) at passage 12, which was rare mutation form and had not been reported. At the same time, Y188C (TAT-->TGT) mutation appeared at passage 10. For JB26, there was a L100I (TTA-->ATA) mutation at passage 10. In a word, JB25 and JB26 showed a low genetic barrier to the development of resistance, and the resistance to JB26 developed slower than JB25. The mutations selected by JB25 and JB26 were mainly associated with codons 188 and 100 of HIV-1 reverse transcriptase.
Amino Acid Sequence ; Amino Acid Substitution ; Anti-HIV Agents ; pharmacology ; Cell Line ; Codon ; Drug Resistance, Viral ; HIV Reverse Transcriptase ; antagonists & inhibitors ; genetics ; HIV-1 ; drug effects ; enzymology ; genetics ; Humans ; Mutation ; Reverse Transcriptase Inhibitors ; pharmacology

Nucleoside reverse transcriptase inhibitors which act as a major component of highly active antiretroviral therapy regimens are widely used in treatment of Acquired Immune Deficiency Syndrome. However, the emergence of drug-resistant variants of HIV-1 severely limits the effectiveness of these drugs. Many drug resistance mutations confer a fitness cost, which can be partially overcome by compensatory mutations or other molecular mechanisms. This review focuses on the impacts of resistance mutations emerging during treatment with nucleoside reverse transcriptase inhibitors on viral fitness, and inter actions between these mutations.
Animals ; Drug Resistance, Viral ; HIV Infections ; drug therapy ; virology ; HIV Reverse Transcriptase ; antagonists & inhibitors ; genetics ; metabolism ; HIV-1 ; drug effects ; enzymology ; genetics ; physiology ; Humans ; Mutation ; Nucleosides ; therapeutic use ; Reverse Transcriptase Inhibitors ; therapeutic use

Current in vitro assays for the activity of HIV-RT (reverse transcriptase) require radio-labeled or chemically modified nucleotides to detect reaction products. However, these assays are inherently end-point measurements and labor intensive. Here we describe a novel non-radioactive assay based on the principle of pyrosequencing coupled-enzyme system to monitor the activity of HIV-RT by indirectly measuring the release of pyrophosphate (PP(i)), which is generated during nascent strand synthesis. The results show that our assay could monitor HIV-RT activity with high sensitivity and is suitable for rapid high-throughput drug screening targeting anti-HIV therapies due to its high speed and convenience. Moreover, this assay can be used to measure primase activity in an easy and sensitive manner, which suggests that this novel approach could be wildly used to analyze the activity of PP(i)-generated and ATP-free enzyme reactions.
Anti-HIV Agents ; pharmacology ; Colorimetry ; Diphosphates ; analysis ; metabolism ; Drug Evaluation, Preclinical ; HIV ; drug effects ; enzymology ; HIV Reverse Transcriptase ; analysis ; antagonists & inhibitors ; metabolism ; Humans ; In Vitro Techniques ; Nevirapine ; pharmacology ; Reverse Transcriptase Inhibitors ; pharmacology ; Sequence Analysis, DNA ; Thymine Nucleotides ; metabolism

OBJECTIVETo investigate the drug resistance of HIV patients to the HIV-1 CRF01_AE and CRF07_BC strains in Sichuan province during 2010 to 2013.

METHODS1.5 ml of plasma were collected from AIDS patients who had been receiving anti-retroviral treatment for over 6 months but still had a HIV-1 virus load of over 1 000 copies/ml from January 1, 2010 to December 31, 2013 in Sichuan province. Genetic analysis of the HIV-1 pol gene was performed using self-established method, and patients with a positive drug-resistant HIV-1 pol gene mutation were included. HIV-1 poly gene was successfully sequenced for a total of 1 213 patients. Drug resistance of different HIV-1 strains was compared with χ2 test or Fisher exact test.

RESULTS558 cases (46.0%) of the 1 213 successfully sequenced patients were infected by HIV-1-strains with drug-resistant mutations, including 327 cases (58.6%) infected by CRF01_AE strain, 126 (22.6%) by CRF07_BC strain, 46 (8.2%) by CRF08_BC strain, 33 (5.9%) by B strain, 4 (0.7%) by C strain, 1 (0.2%) by CRF02_AG strain, and 21 (3.8%) by unidentified strains. Drug-resistant mutation analysis revealed that L33, F116, L74, Q151, and T69 resistance mutations occurred only in the CRF01_AE strain, while A71, K43, and Q58 resistance mutations occurred only in the CRF07_BC strain; in nuclear nucleoside reverse transcriptase inhibitors (NRTIs) and non nucleoside reverse transcriptase inhibitors (NNRTIs), CRF01_AE subtype strains showed highly resistant rate were higher than CRF07_BC, CRF08_BC and B subtype strains, with the differences were statistically significant (P<0.05).

CONCLUSIONThe drug-resistant HIV-1 strains in Sichuan mainly included the CRF01_AE and CRF07_BC strains, which had different resistance mutations.

Base Sequence ; Drug Resistance, Viral ; Genes, pol ; HIV Infections ; HIV-1 ; Humans ; Mutation ; Reverse Transcriptase Inhibitors ; Viral Load