HIV and AIDS remain as the crucial global health concern, therefore, research and development of novel anti-HIV-1 chemical therapeutics is still of paramount significance, which may be illuminated by cases of successful marketed drugs. Herein, we document the discovery and biological profile of new anti-HIV-1 drugs approved by FDA between 2005 and 2008 and some drug candidates are also discussed.
Acquired Immunodeficiency Syndrome ; drug therapy ; Anti-HIV Agents ; chemistry ; pharmacology ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Protease Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Reverse Transcriptase Inhibitors ; chemistry ; pharmacology ; therapeutic use

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (AIDS). After over 26 years of efforts, there is still not a therapeutic cure or an effective vaccine against HIV/AIDS. The clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART). Although highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs. Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors, NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibitors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists). Here, we intend to provide updated information of currently available antiretroviral drugs for ART to promote the development of novel anti-HIV-1 drugs.
Acquired Immunodeficiency Syndrome ; drug therapy ; Anti-HIV Agents ; chemistry ; pharmacology ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Protease Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Reverse Transcriptase Inhibitors ; chemistry ; pharmacology ; therapeutic use

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.
Anti-HIV Agents ; adverse effects ; pharmacology ; therapeutic use ; Antiretroviral Therapy, Highly Active ; Cyclohexanes ; chemistry ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; HIV Envelope Protein gp41 ; chemistry ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Protease Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Reverse Transcriptase ; chemistry ; pharmacology ; therapeutic use ; HIV-1 ; drug effects ; physiology ; Humans ; Molecular Structure ; Peptide Fragments ; chemistry ; therapeutic use ; Pyrrolidinones ; chemistry ; pharmacology ; therapeutic use ; Raltegravir Potassium ; Saquinavir ; chemistry ; pharmacology ; therapeutic use ; Triazoles ; chemistry ; pharmacology ; therapeutic use ; Virus Replication ; drug effects ; Zidovudine ; chemistry ; pharmacology ; therapeutic use

Plant active components characterized of many different structures and activities on multiple targets, have made them to be the important sources of inhibitors on HIV-1. For finding leading compounds with new structure against HIV-1, three key HIV-1 replicative enzymes (reverse transcriptase, protease and integrase) were used as screening models. The in vitro activities of 45 plant derived components isolated from Schisandraceae, Rutaceae and Ranunculaceae were reported. Within twelve triterpene components isolated, eight compounds were found to inhibit HIV-1 protease, in these eight active compounds, kadsuranic acid A (7) and nigranoic acid (8), inhibited both HIV-1 protease and integrase; Among fifteen lignans, meso-dihydroguaiaretic acid (15) and kadsurarin (16) were active on HIV-1 reverse transcriptase, and 4, 4-di(4-hydroxy-3-methoxyphenly)-2, 3-dimethylbutanol (13) active on HIV-1 integrase. All of the six alkaloids, seven flavones, and five others compounds were not active or only with low activities against HIV-1 replicative enzymes. Further studies of the triterpene components showing strong inhibitory activities on HIV-1 were warranted.
Alkaloids ; chemistry ; isolation & purification ; pharmacology ; Anti-HIV Agents ; chemistry ; isolation & purification ; pharmacology ; Drugs, Chinese Herbal ; chemistry ; isolation & purification ; pharmacology ; Flavones ; chemistry ; isolation & purification ; pharmacology ; Guaiacol ; analogs & derivatives ; chemistry ; isolation & purification ; pharmacology ; HIV Integrase ; drug effects ; HIV Protease ; drug effects ; HIV Reverse Transcriptase ; antagonists & inhibitors ; Lignans ; chemistry ; isolation & purification ; pharmacology ; Plants, Medicinal ; chemistry ; Ranunculaceae ; chemistry ; Rutaceae ; chemistry ; Schisandraceae ; chemistry ; Triterpenes ; chemistry ; isolation & purification ; pharmacology

CCR5, a membrane protein on cell surface, is a member of the G protein-coupled receptor superfamily and one of the major co-receptors for HIV-1 infection. The roles of CCR5 in HIV-1 infection have been elucidated since 1996. Because of the biological nature of CCR5, it has became a molecular target for the novel drugs against HIV-1. Antagonists for CCR5 could be grouped as following, chemokine derivatives, small molecule non-peptide compounds, monoclonal antibodies and peptides. The latest progress in this field is reviewed in this article.
Anti-HIV Agents ; pharmacology ; Antibodies, Monoclonal ; CCR5 Receptor Antagonists ; Drug Design ; HIV Infections ; metabolism ; HIV-1 ; drug effects ; Receptors, CCR5 ; drug effects ; Receptors, Chemokine ; drug effects

This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors. The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors. Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy. The drug resistance associated with some of the entry inhibitors will also be discussed.
Anti-HIV Agents ; chemistry ; pharmacology ; therapeutic use ; CCR5 Receptor Antagonists ; CD4 Antigens ; drug effects ; Cyclohexanes ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; HIV Envelope Protein gp120 ; pharmacology ; HIV Envelope Protein gp41 ; pharmacology ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV-1 ; drug effects ; Humans ; Molecular Structure ; Peptide Fragments ; pharmacology ; therapeutic use ; Receptors, CCR5 ; physiology ; Receptors, CXCR4 ; antagonists & inhibitors ; Receptors, Chemokine ; drug effects ; Triazoles ; pharmacology ; therapeutic use

Animals ; Anti-HIV Agents ; chemistry ; pharmacology ; Furans ; pharmacology ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; HIV-1 ; drug effects ; Humans ; Keto Acids ; chemistry ; pharmacology ; Molecular Structure ; Naphthyridines ; pharmacology ; Triazoles ; pharmacology

HIV-1 integrase (IN) is an essential enzyme for retroviral replication. There is no analogue for this enzyme in human cells so that inhibition of IN will not bring strong effect on human body. Thus, HIV-1 IN has become a rational target for therapy of AIDS. This review provides a comprehensive report of alpha, gamma-diketo IN inhibitors discovered in recent years. Compilation of such data will prove to be beneficial in developing QSAR, pharmacophore hypothesis generation and validation, virtual screening and synthesis of compounds with higher activity.
Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; HIV Integrase ; chemistry ; physiology ; HIV Integrase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; HIV-1 ; drug effects ; Humans ; Keto Acids ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; Quantitative Structure-Activity Relationship

AIM: To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder (Thymelaeaceae). METHODS: The anti-HIV activities of wikstroelide M against different HIV strains were evaluated by cytopathic effect assay and p24 quantification assay with ELISA. The inhibitory effect of wikstroelide M on HIV reverse transcription was analyzed by real-time PCR and ELISA. The effect of wikstroelide M on HIV-1 integrase nuclear translocation was observed with a cell-based imaging assay. The effect of wikstroelide M on LEDGF/p75-IN interaction was assayed by molecular docking. RESULTS: Wikstroelide M potently inhibited different HIV-1 strains, including HIV-1IIIB, HIV-1A17, and HIV-19495, induced a cytopathic effect, with EC50 values ranging from 3.81 to 15.65 ng·mL⁻¹. Wikstroelide M also had high inhibitory activities against HIV-2ROD and HIV-2CBL-20-induced cytopathic effects with EC50 values of 18.88 and 31.90 ng·mL⁻¹. The inhibitory activities of wikstroelide M on the three HIV-1 strains were further confirmed by p24 quantification assay, with EC50 values ranging from 15.16 to 35.57 ng·mL⁻¹. Wikstroelide M also potently inhibited HIV-1IIIB induced cytolysis in MT-4 cells, with an EC50 value of 9.60 ng·mL⁻¹. The mechanistic assay showed that wikstroelide M targeted HIV-1 reverse transcriptase and nuclear translocation of integrase through disrupting the interaction between integrase and LEDGF/p75. CONCLUSION Wikstroelide M may be a potent HIV-1 and HIV-2 inhibitor, the mechanisms of action may include inhibition of reverse trascriptase activity and inhibition of integrase nuclear translocation through disrupting the interaction between integrase and LEDGF/p75.
Anti-HIV Agents ; pharmacology ; therapeutic use ; Cell Line ; Daphne ; chemistry ; Diterpenes ; pharmacology ; HIV Infections ; drug therapy ; virology ; HIV Integrase ; metabolism ; HIV Integrase Inhibitors ; pharmacology ; therapeutic use ; HIV Reverse Transcriptase ; antagonists & inhibitors ; HIV-1 ; drug effects ; enzymology ; HIV-2 ; drug effects ; Humans ; Intercellular Signaling Peptides and Proteins ; metabolism ; Phytotherapy ; Plant Extracts ; pharmacology ; therapeutic use ; Virus Integration ; drug effects ; Virus Replication ; drug effects

OBJECTIVEFrequency, type and clinical implications on protease and reverse transcriptase drug resistance mutations were investigated and phylogenetic analysis in antiretroviral drug-naïve AIDS patients was carried out in Henan province.

METHODS45 plasma samples were separated from the anticoagulatory whole blood, from which reverse transcription-polymerase chain reaction technique was used to amplify the partial pol gene. The sequences were analysed for genotypic antiretroviral resistance and phylogenetic relation through landing the websites http://hivdb.stanford.edu and http://hiv-web.lanl.gov, under BioEdit and DNAClub software.

RESULTSPartial pol sequences of 36 samples were successfully amplified. The major mutation rate of resistance to protease was 8.3% (3/36), including types D30A, V32A, G73C and V82A. Minor mutation rate of resistance was 100%, including types of L63PS (36/36), I93L (35/36), V77IL (34/36), A71IVT (10/36) and D60E (2/36). The mutation rate of resistance to reverse transcriptase was 38.9% (14/36). Mutation-scoring and clinical implication clewed drug resistance rates were 5.6% (2/36) and 22.2% (8/36) to protease inhibitors and reverse transcriptase inhibitors respectively, while 1 sample was potentially low-level resistant to all of the protease inhibitors and 3 samples to part of the reverse transcriptase inhibitors. Phylogenetic analysis revealed that the pol gene of 36 samples were highly homologous and having a near relative to B.US.83.RF ACC M17451. 36 samples seemed to have the same infection source while their resistance mutations were not due to drug-resistant virus infection but to the evolving of virus in vivo.

CONCLUSIONMost of the antiretroviral drug-naïve AIDS patients in Henan province were sensitive to the currently available antiviral medicine, but antiviral treatment must be in accordance with the strict procedure and to keep better adherence, to avoid the epidemics caused by drug-resistant virus.

Acquired Immunodeficiency Syndrome ; genetics ; Adult ; Anti-HIV Agents ; pharmacology ; China ; Drug Resistance, Viral ; genetics ; Female ; Genes, pol ; genetics ; Genotype ; HIV Protease ; genetics ; HIV Protease Inhibitors ; pharmacology ; Humans ; Male ; Mutation ; Phylogeny ; RNA-Directed DNA Polymerase ; genetics ; Reverse Transcriptase Inhibitors ; pharmacology