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Results for “Integrase Inhibitors”

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At least 19 recordsLinked to original sources

PubMed2004

Synthesis and anti-HIV activity of some [Nucleoside Reverse Transcriptase Inhibitor]-C5'-linker-[Integrase Inhibitor] heterodimers as inhibitors of HIV replication.

Selected for their expected ability to inhibit HIV replication, a series of eight heterodimers containing a Nucleoside Reverse Transcriptase Inhibitor (NRTI) and an Integrase Inhibitor (INI), bound by a linker, were designed and synthesized. For the NRTIs, d4U, d2U and d4T were chosen. For the INIs, 4-[1-(4-fluorobenzyl)-1H-pyrrol-2-yl]-2,4-dioxobutyric acid (6) and 4-(3,5-dibenzyloxyphenyl)-2,4-dioxobutyric acid (9) (belonging to the beta-diketo acids class) were chosen. The conjugation of the two different inhibitors (NRTI and INI) was performed using an amino acid (glycine or beta-alanine) as a cleavable linker.

Anti-HIV Agents↗

PubMed2006

A platform for designing HIV integrase inhibitors. Part 1: 2-hydroxy-3-heteroaryl acrylic acid derivatives as novel HIV integrase inhibitor and modeling of hydrophilic and hydrophobic pharmacophores.

We present a novel series of HIV integrase inhibitors, showing IC(50)s ranging from 0.01 to over 370microM in an enzymatic assay. Furthermore, pharmacophore modeling study for the inhibitors was carried out to elucidate the structure-activity relationships. Finally, we found a 3D-pharmacophore model, which is composed of a hydrophilic and a hydrophobic domain, providing valuable information for designing other novel types of integrase inhibitors.

Acrylates↗

PubMedDate not supplied

[Computer search for novel HIV-1 integrase inhibitors].

HIV-1 integrase is the third enzyme essential for viral replication. It represents an attractive target for new anti-HIV drugs. Diketo acids represent the most prospective class of integrase inhibitors; one of them (S1360) is currently under clinical trials. We prepared the training set containing 90 diketoacid derivatives and performed re-training of computer program PASS. Average accuracy of prediction in LOO cross-validation for HIV-1 integrase inhibitors was shown to be 99%. We selected eight new potential HIV-1 integrase inhibitors among about the 700,000 substances from the databases of commercially available chemicals; anti-integrase activity was found experimentally in two selected compounds.

Anti-HIV Agents↗

PubMed2006

A platform for designing HIV integrase inhibitors. Part 2: a two-metal binding model as a potential mechanism of HIV integrase inhibitors.

We propose a two-metal binding model as a potential mechanism of chelating inhibitors against HIV integrase (HIV IN) represented by 2-hydroxy-3-heteroaryl acrylic acids (HHAAs). Potential inhibitors would bind to two metal ions in the active site of HIV IN to prevent human DNA from undergoing the integration reaction. Correlation of the results of metal (Mg(2+) and Mn(2+)) titration studies with HIV IN inhibition for a series of active and inactive compounds provides support for the model. Results suggest Mg(2+) is an essential cofactor for chelating inhibitors.

Acrylates↗

PubMed2003

Caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors.

HIV-1 integrase (IN) is an essential enzyme for retroviral replication and a rational target for the design of anti-AIDS drugs. In the present study, we have designed, synthesized and tested a series of caffeoyl naphthalenesulfonamide derivatives as HIV integrase inhibitors. Among these compounds, we found that HIV integrase inhibitory activities of compounds III-3 and III-4 were more potent than L-chicoric acid (IC(50)=11.8 microg/mL) and others were comparable to L-chicoric acid. Furthermore, the structure-activity relationships of these compounds were studied. The information gathered from this paper will be useful in the development and design of HIV-1 integrase inhibitors in the future.

Anti-HIV Agents↗

PubMed2003

Catechol-substituted L-chicoric acid analogues as HIV integrase inhibitors.

HIV integrase catalyzes the integration of HIV DNA copy into the host cell DNA, which is essential for the production of progeny viruses. L-Chicoric acid and dicaffeoylquinic acids, isolated from plants, are well known potent inhibitors of HIV integrase. The common structural features of these inhibitors are caffeic acid derivatives connected to tartaric acid or quinic acid through ester bonds. In the present study, we have synthesized and tested the inhibitory activities of a new type of HIV IN inhibitors, which has catechol groups in place of caffeoyl groups in the structure of L-chicoric acid. Upon substitution of catechol groups at succinic acid, pyrrole-dicarboxylic acid, maleimide or maleic anhydride, the inhibitory activities (IC(50)=3.8-23.6 microM) were retained or remarkably increased when compared to parent compound L-chicoric acid (IC(50)=13.7 microM).

Caffeic Acids↗

PubMed2006

Designing HIV integrase inhibitors--shooting the last arrow.

The arsenal of drugs in the fight against AIDS is rapidly diminishing as the HIV becomes resistant to the available reverse transcriptase and protease inhibitors. After killing millions all over the world, the virus is still on the rampage and hence the pharmaceutical industry is resorting to the development of inhibitors of integrase. This seems to be the last arrow in the quiver of potential drug leads to combat the deadly infection. Several classes of HIV integrase inhibitors have been reported to date; however, none is clinically useful. This review details the existing knowledge of the biological functions of the HIV-1 integrase with the focus on its available inhibitors, their disadvantages, and the current trends in designing novel compounds as anti-integrase.

Combinatorial Chemistry Techniques↗

PubMed2005

Nef expressed from human immunodeficiency virus type 1 extrachromosomal DNA downregulates CD4 on primary CD4+ T lymphocytes: implications for integrase inhibitors.

Recently developed integrase inhibitors targeting the HIV-1 integrase (IN) protein block integration of HIV DNA in the target cell, preventing subsequent virus replication. In the absence of integration, viral DNA is shunted towards the formation of extrachromosomal DNA (E-DNA). Although HIV-1 E-DNA does not support productive replication, it is transcriptionally active and produces viral proteins. However, the significance of E-DNA in virus replication and pathogenesis is poorly understood. In this study, the functional activity of the HIV-1 Nef protein expressed in the absence of viral integration was analysed. Using both a recombinant HIV-1 IN defective virus and a diketo acid IN inhibitor, evidence was provided showing that Nef expressed from E-DNA downregulates CD4 surface expression on primary CD4(+) T lymphocytes. These results suggest that proteins expressed in the absence of integration may have potential clinical consequences, an issue that should be further explored with the introduction of IN inhibitors.

CD4 Antigens↗

PubMed2006

Probing HIV-1 integrase inhibitor binding sites with position-specific integrase-DNA cross-linking assays.

HIV-1 integrase binds site-specifically to the ends of the viral cDNA. We used two HIV-1 integrase-DNA cross-linking assays to probe the binding sites of integrase inhibitors from different chemical families and with different strand transfer selectivities. The disulfide assay probes cross-linking between the integrase residue 148 and the 5'-terminal cytosine of the viral cDNA, and the Schiff base assay probes cross-linking between an integrase lysine residue and an abasic site placed at selected positions in the viral cDNA. Cross-linking interference by eight integrase inhibitors shows that the most potent cross-linking inhibitors are 3'-processing inhibitors, indicating that cross-linking assays probe the donor viral cDNA (donor binding site). In contrast, strand transfer-selective inhibitors provide weak cross-linking interference, consistent with their binding to a specific acceptor (cellular DNA) site. Docking and crystal structure studies illustrate specific integrase-inhibitor contacts that prevent cross-linking formation. Four inhibitors that prevented Schiff base cross-linking to the conserved 3'-terminal adenine position were examined for inhibition at various positions within the terminal 21 bases of the viral cDNA. Two of them selectively inhibited upper strand cross-linking, whereas the other two had a more global effect on integrase-DNA binding. These findings have implications for elucidating inhibitor binding sites and mechanisms of action. The cross-linking assays also provide clues to the molecular interactions between integrase and the viral cDNA.

Binding Sites↗

PubMed2006

A historical sketch of the discovery and development of HIV-1 integrase inhibitors.

The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor 'integration' of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the beta-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review reconstructs (in the general context of the history of AIDS research) the principal steps that led to the integrase inhibitors currently in clinical trials, and discusses possible future directions.

Anti-HIV Agents↗

PubMed2005

Integrase inhibitors to treat HIV/AIDS.

HIV integrase is a rational target for treating HIV infection and preventing AIDS. It took approximately 12 years to develop clinically usable inhibitors of integrase, and Phase I clinical trials of integrase inhibitors have just begun. This review focuses on the molecular basis and rationale for developing integrase inhibitors. The main classes of lead compounds are also described, as well as the concept of interfacial inhibitors of protein-nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors.

Africa South of the Sahara↗

PubMed2001

The failure of HAART to cure the HIV-1/AIDS complex. Suggestions to add integrase inhibitors as complementary virostatics, and to replace their continuous long combination applications by short sequences differing by drug rotations.

While the intensive virostatic combinations applied according to the conventional models (such as HAART), based only on the attacks of two HIV-1 targets, retrotranscriptase and protease, and applied in a long and continuous fashion, a) are notably toxic, b) do not correct completely the abnormal immunologic parameters, and c) are followed by particularly severe and poorly sensitive relapses in case of discontinuation, we propose to the 'AIDS treatment headquarters' to include in their failing strategy the two original features which we have included in the treatment of a cohort of a dozen patients, treatment applied at all but one AIDS stage. We attack one more HIV-1 target than the conventional protocols do, by adding inhibitors of integrase; we apply the combinations of virostatics, comprising inhibitors of the three targets, in short sequences (of 3 weeks), between which the analogues are changed inside each series. The first patient of the cohort started his treatment 8.5 years ago, and the entries of the others into it have been at random and not randomized. All patients are alive today and in excellent condition.

AIDS-Related Complex↗

PubMed1997

Discovery of HIV-1 integrase inhibitors by pharmacophore searching.

Based upon a class of known HIV-1 integrase inhibitors, several pharmacophore models were proposed from molecular modeling studies and validated using a 3D database of 152, compounds for which integrase assay data are known. Using the most probable pharmacophore model as the query, the NCI 3D database of 206,876 compounds was searched, and 340 compounds that contain the pharmacophore query were identified. Twenty-nine of these compounds were selected and tested in the HIV-1 integrase assay. This led to the discovery of 10 novel, structurally diverse HIV-1 integrase inhibitors, four of which have an IC50 value less than 30 microM and are promising lead compounds for further HIV-1 integrase inhibitor development.

4-Hydroxycoumarins↗

PubMed2003

Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions.

HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. A great number of HIV-1 integrase inhibitors have been described in the last decade and numerous reviews have been published. The biochemical mechanism of HIV-1 DNA integration, the enzyme structure and the possible targets for drug intervention have been thoroughly analyzed. Structure-based drug design including both ligand-based (pharmacophore) and target-based (docking) methods has also been discussed. The recent report of the crystal structure of HIV-1 integrase core domain with an inhibitor has given a new boost leading in the last two years to the emergence of diketoacids (DKAs). To date, with the dicaffeoyltartaric acids they are the only two classes of molecules that meet the criteria necessary to be considered lead molecules in the search for clinically useful inhibitors of HIV-1 integrase. After a survey of the function and the structure of this enzyme and the different available assays for the identification of new IN inhibitors, structure-activity relationships of HIV-1 integrase inhibitors that are expected to interact with the active site (or in its vicinity) will be discussed with emphasis on their different proposed mechanisms of action.

Anti-HIV Agents↗

PubMed2004

De novo design and synthesis of HIV-1 integrase inhibitors.

Existing AIDS therapies are out of reach for most HIV-infected people in developing countries and, where available, they are limited by their toxicity and their cost. New anti-HIV agents are needed urgently to combat emerging viral resistance and reduce the side effects associated with currently available drugs. Toward this end, LeapFrog, a de novo drug design program was used to design novel, potent, and selective inhibitors of HIV-1 integrase. The designed compounds were synthesized and tested for in vitro inhibition of HIV-1 integrase. Out of the 25 compounds that were designed, and synthesized, four molecules (compounds 23, 26, 43, and 59) showed moderate to low inhibition of HIV-1 integrase for 3'-processing and 3'-strand transfer activities. Nonetheless, these compounds possess structural features not seen in known HIV-1 integrase inhibitors and thus can serve as excellent leads for further optimization of anti-HIV-1 integrase activity.

HIV Integrase Inhibitors↗

PubMed2004

Integrase inhibitors and cellular immunity suppress retroviral replication in rhesus macaques.

We describe the efficacy of L-870812, an inhibitor of HIV-1 and SIV integrase, in rhesus macaques infected with the simian-human immunodeficiency virus (SHIV) 89.6P. When initiated before CD4 cell depletion, L-870812 therapy mediated a sustained suppression of viremia, preserving CD4 levels and permitting the induction of virus-specific cellular immunity. L-870812 was also active in chronic infection; however, the magnitude and durability of the effect varied in conjunction with the pretreatment immune response and viral load. These studies demonstrate integrase inhibitor activity in vivo and suggest that cellular immunity facilitates chemotherapeutic efficacy in retroviral infections.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Discovery and structure-activity relationship studies of a unique class of HIV-1 integrase inhibitors.

HIV-1 integrase (IN) is an essential enzyme for viral replication and a validated target for the development of drugs against AIDS. Currently there are no approved drugs that target IN. However, new IN inhibitors are under clinical investigation. As more IN inhibitors enter human drug trials, there is a growing need for the design of novel lead compounds with diverse structural scaffolds and promising pharmacokinetic properties to counteract the difficulties observed with first-generation IN inhibitors. We have identified a novel class of IN inhibitors through the systematic exploration of structure-activity relationships in a series of linomide analogues. The predicted bound conformation of the most active analogues inside the IN active site also supports the observed structure-activity correlation in this new compound class.

Base Sequence↗

PubMed2006

Mining the NCI antiviral compounds for HIV-1 integrase inhibitors.

HIV-1 integrase (IN) is an essential enzyme for effective viral replication and is a validated target for the development of antiretroviral drugs. Currently, there are no approved drugs targeting this enzyme. In this study, we have identified 11 structurally diverse small-molecule inhibitors of IN. These compounds have been selected by mining the moderately active antiviral molecules from a collection of 90,000 compounds screened by the National Cancer Institute (NCI) Antiviral Program. These compounds, which were screened at the NCI during the past 20 years, resulted in approximately 4000 compounds labeled as 'moderately active.' In our study, chalcone 11 shows the most potent activity with an IC(50) of 2+/-1 microM against purified IN in the presence of both Mn(2+) and Mg(2+) as cofactors. Docking simulations using the 11 identified inhibitors as a training set have elucidated two unique binding areas within the active site: the first encompasses the conserved D64-D116-E152 motif, while the other involves the flexible loop region formed by amino acid residues 140-149. The tested inhibitors exhibit favorable interactions with important amino acid residues through van der Waals and H-bonding contacts.

Anti-HIV Agents↗