The dawn of a new treatment. A look at experimental HIV integrase inhibitors.
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Clinical Trials as Topic↗
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[HIV integrase inhibitors: a promising development in AIDS research].
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Acquired Immunodeficiency Syndrome↗
Hydrazide-containing inhibitors of HIV-1 integrase.
Inhibitors of HIV integrase are currently being sought as potential new therapeutics for the treatment of AIDS. A large number of inhibitors discovered to date contain the o-bis-hydroxy catechol structure. In an effort to discover structural leads for the development of new HIV integrase inhibitors which do not rely on this potentially cytotoxic catechol substructure, NSC 310217 was identified using a three-point pharmacophore search based on its assigned structure N-(2-hydroxybenzoyl)-N-(2-hydroxy-3-phenoxypropyl)hydrazine (1). When a sample of NSC 310217 was obtained from the NCI repository, it was shown to exhibit potent inhibition of HIV-1 integrase (3'-processing IC50 = 0.6 microgram/mL). In work reported herein, we demonstrate that NSC 310217, rather than containing 1, which has no inhibitory potency against HIV-1 integrase, is comprised of roughly a 1:1 mixture of N-(2-hydroxybenzoyl)-N'-(2-hydroxy-3-phenoxypropyl)hydrazine (6) and N,N'-bis-salicylhydrazine 7, with all inhibitory potency residing with compound 7(IC50 = 0.7 microM for strand transfer). In subsequent structure-activity studies on 7, it is shown that removing a single amide carbonyl (compound 14, IC50 = 5.2 microM) or replacing one aromatic ring system with a naphthyl ring (compound 19, IC50 = 1.1 microM) can be accomplished with little loss of inhibitory potency. Additionally, replacing a single hydroxyl with a sulfhydryl (compound 23, IC50 = 5.8 microM) results in only moderate loss of potency. All other modifications examined, including the replacement of a single hydroxyl with an amino group (compound 22), resulted in complete loss of potency. Being potent, structurally simple, and non-catechol-containing, compounds such as 7 and 14 may provide useful leads for the development of a new class of HIV integrase inhibitor.
Databases, Factual↗
Styrylquinoline derivatives: a new class of potent HIV-1 integrase inhibitors that block HIV-1 replication in CEM cells.
On the basis of the fact that several polynucleotidyl transferases, related to HIV integrase, contain in their active site two divalent metal cations, separated by ca. 4 A, new potential HIV integrase inhibitors were designed, in which a quinoline substructure is linked to an aryl nucleus possessing various hydroxy substitution patterns, by means of an ethylenic spacer. Although the most active compounds contain the catechol structure, this group is not essential for the activity, since compound 21 that lacks such a moiety is a potent drug, implicating the presence of a different pharmacophore. The most promising styrylquinolines thus synthesized inhibit HIV-1 integrase in vitro at micromolar or submicromolar concentrations and block HIV replication in CEM cells, with no significant cellular toxicity in a 5-day period assay. These inhibitors are active against integrase core domain-mediated disintegration, suggesting that fragment 50-212 is their actual target. These new styrylquinolines may provide lead compounds for the development of novel antiretroviral agents for AIDS therapeutics, based upon inhibition of HIV integrase. They might also be used in the elucidation of the mechanism of inhibition of this enzyme; e.g., they could serve as candidates for cocrystallization studies with HIV integrase.
Anti-HIV Agents↗
Three-dimensional quantitative structure-activity relationship (QSAR) of HIV integrase inhibitors: a comparative molecular field analysis (CoMFA) study.
We present the results from a comparative molecular field analysis (CoMFA) of a set of flavone analogs that inhibit HIV-1 integrase-mediated cleavage (3'-processing step) and integration (strand transfer step) in vitro. The results indicate a strong correlation between the inhibitory activity of these flavones and the steric and electrostatic fields around them. CoMFA quantitative structure-activity relationship models with considerable predictive ability (cross-validated r2 as high as 0.8) were obtained.
Chemical Phenomena↗
Human immunodeficiency virus type 1 (HIV-1) integrase: resistance to diketo acid integrase inhibitors impairs HIV-1 replication and integration and confers cross-resistance to L-chicoric acid.
The diketo acids are potent inhibitors of human immunodeficiency virus (HIV) integrase (IN). Mutations in IN, T66I, S153Y, and M154I, as well as T66I-S153Y and T66I-M154I double mutations, confer resistance to diketo acids (D. J. Hazuda et al., Science 287:646-650, 2000). The effects of these IN mutations on viral replication, enzymatic activity, and susceptibility to other HIV inhibitors are reported herein. By immunofluorescence assay and real-time PCR, all mutant viruses demonstrated a modest delay in viral spread compared to that of reference HIV. These viruses also showed a statistically significant defect in integration without defects in reverse transcription. Recombinant IN containing S153Y, T66I, and M154I-T66I mutations had an approximately twofold decrease in both disintegration and 3'-end-processing-strand transfer activities in vitro. In contrast, IN containing M154I demonstrated a greater than twofold increase in specific activity in both reactions. All mutant HIVs were resistant to l-chicoric acid, a dicaffeoyltartaric acid IN inhibitor, both in tissue culture and in biochemical assays, yet remained susceptible to the reverse transcriptase inhibitors zidovudine and nevirapine. Thus, IN mutations conferring resistance to the diketo acids can yield integration defects, attenuated catalysis in vitro, and cross-resistance to l-chicoric acid.
Caffeic Acids↗
Thalassiolins A-C: new marine-derived inhibitors of HIV cDNA integrase.
Human immunodeficiency virus (HIV) replication requires integration of viral cDNA into the host genome, a process mediated by the viral enzyme integrase. We describe a new series of HIV integrase inhibitors, thalassiolins A-C (1-3), isolated from the Caribbean sea grass Thalassia testudinum. The thalassiolins are distinguished from other flavones previously studied by the substitution of a sulfated beta-D-glucose at the 7-position, a substituent that imparts increased potency against integrase in biochemical assays. The most active of these molecules, thalassiolin A (1), displays in vitro inhibition of the integrase catalyzed strand transfer reaction (IC50=0.4 microM) and an antiviral IC50 of 30 microM. Molecular modeling studies indicate a favorable binding mode is probable at the catalytic core domain of HIV-1 integrase.
Binding Sites↗
Synthesis of novel thiazolothiazepine based HIV-1 integrase inhibitors.
Thiazolothiazepines are among the smallest and most constrained inhibitors of human immunodeficiency virus type-1 integrase (HIV-1 IN) inhibitors (J. Med. Chem. 1999, 42, 3334). Previously, we identified two thiazolothiazepines lead IN inhibitors with antiviral activity in cell-based assays. Structural optimization of these molecules necessitated the design of easily synthesizable analogs. In order to design similar molecules with least number of substituent, herein we report the synthesis of 10 novel analogs. One of the new compounds (1) exhibited similar potency as the reference compounds, confirming that a thiazepinedione fused to a naphthalene ring system is the best combination for the molecule to accommodate into the IN active site. Thus, the replacement of sulfur in the thiazole ring with an oxygen does not seem considerably affect potency. On the other hand, the introduction of an extra methyl group at position 1 of the polycyclic system or the shift from a thiazepine to an oxazepine skeleton decreased potency. In order to understand their mode of interactions with IN active site, we docked all the compounds onto the previously reported X-ray crystal structure of IN. We observed that compounds 7-9 occupied an area close to D64 and Mg(2+) and surrounded by amino acid residues K159, K156, N155, E152, D116, H67, and T66. The oxygen atom of the oxazolo ring of 7 and 8 could chelate Mg(2+). These results indicate that the new analogs potentially interact with the highly conserved residues important for IN catalytic activities.
Anti-HIV Agents↗
2,6-Bis(3,4,5-trihydroxybenzylydene) derivatives of cyclohexanone: novel potent HIV-1 integrase inhibitors that prevent HIV-1 multiplication in cell-based assays.
A number of 2,6-bisbenzylidenecyclohexane-1-one derivatives have been synthesized and tested as HIV-1 integrase (IN) inhibitors with the aim of obtaining compounds capable to elicit antiviral activity at non-cytotoxic concentrations in cell-based assays. 3,5-Bis(3,4,5-trihydroxybenzylidene)-4-oxocyclohexaneacetic acid (20d) resulted one of the most potent and selective derivatives in acutely infected MT-4 cells (EC(50) and CC(50) values of 2 and 40 microM, respectively). In enzyme assays with recombinant HIV-1 integrase (rIN), this compound proved able to inhibit both 3'-processing and disintegration with IC(50) values of 0.2 and 0.5 microM, respectively. In order to develop a model capable to predict the anti HIV-IN activity and useful to design novel derivatives, we performed a comparative molecular field analysis (CoMFA) like 3-D-QSAR. In our model the ligands were described quantitatively in the GRID program, and the model was optimized by selecting only the most informative variables in the GOLPE program. We found the predictive ability of the model to increase significantly when the number of variables was reduced from 20,925 to 1327. A Q(2) of 0.73 was obtained with the final model, confirming the predictive ability of the model. By studying the PLS coefficients in informative 3-D contour plots, ideas for the synthesis of new compounds could be generated.
Anti-HIV Agents↗
Exploring binding mode for styrylquinoline HIV-1 integrase inhibitors using comparative molecular field analysis and docking studies.
AIM: To understand pharmacophore properties of styrylquinoline derivatives and to design inhibitors of HIV-1 integrase. METHODS: Comparative molecular field analysis (CoMFA) was performed to analyze three-dimensional quantitative structure-activity relationship (3D-QSAR) of styrylquinoline derivatives. Thirty-eight compounds were randomly divided into a training set of 28 compounds and a test set of 10 compounds. The stability of 3D-QSAR models was proved by the analysis of cross-validated and non-cross-validated methods. Moreover, the binding mode of these compounds and integrase was constructed by AutoDock program. RESULTS: The CoMFA model of the training compounds was reasonably predicted with cross-validated coefficient (q2) and conventional (r2) values (up to 0.696 and 0.754). Then the model was validated by the test set. The resulting CoMFA maps visualized structural requirements for the biological activity of these inhibitors. Docking results showed that a carboxyl group at C-7 and a hydroxyl group at C-8 in the quinoline subunit, bound closely to the divalent metal cofactor (Mg2+) around the integrase catalytic site. Moreover, there is a linear correlation between the binding energy of the inhibitors with integrase and their inhibitory effect. CONCLUSIONS: The present study indicated that the CoMFA model together with docking results could give us helpful hints for drug design as well as interpretation of the binding affinity between these inhibitors and integrase.
Binding Sites↗
Chemistry and structure-activity relationship of HIV-1 integrase inhibitor integracide B and related natural products.
Integracides, 4,4-dimethylergostane triterpenoids, are inhibitors of HIV-1 integrase, a critical enzyme in replication of HIV-1. The chemistry and structure-activity relationship of integracide B and related natural products are described. A charged group, e.g., a sulfate, carboxyl, or amino, is required for the HIV-1 integrase activity. These compounds showed HIV-1 integrase activity with IC(50) values in the range 4.8-15 muM and exhibited antiviral activity in a viral spread assay, but with only a small or no therapeutic window.
Anti-HIV Agents↗
Design and synthesis of novel indole beta-diketo acid derivatives as HIV-1 integrase inhibitors.
Diketo acids such as S-1360 (1A) and L-731,988 (2) are potent and selective inhibitors of HIV-1 integrase (IN). A plethora of diketo acid-containing compounds have been claimed in patent literature without disclosing much biological activities and synthetic details (reviewed in Neamati, N. Exp. Opin. Ther. Pat. 2002, 12, 709-724). To establish a coherent structure-activity relationship among the substituted indole nucleus bearing a beta-diketo acid moiety, a series of substituted indole-beta-diketo acids (4a-f and 5a-e) were synthesized. All compounds tested showed anti-IN activity at low micromolar concentrations with varied selectivity against the strand transfer process. Three compounds, the indole-3-beta-diketo acids 5a and 5c, and the parent ester 9c, have shown an antiviral activity in cell-based assays. We further confirmed a keto-enolic structure in the 2,3-position of the diketo acid moiety of a representative compound (4c) using NMR and X-ray crystallographic analysis. Using this structure as a lead for all of our computational studies, we found that the title compounds extensively interact with the essential amino acids on the active site of IN.
Cells, Cultured↗
Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors.
We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.
Carbon Isotopes↗
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↗
Synthesis and biological evaluation of geminal disulfones as HIV-1 integrase inhibitors.
Integration of HIV-1 viral DNA into the host genome is carried out by HIV-integrase (IN) and is a critical step in viral replication. Although several classes of compounds have been reported to inhibit IN in enzymatic assays, inhibition is not always correlated with antiviral activity. Moreover, potent antiviral IN inhibitors such as the chicoric acids do not act upon the intended enzymatic target but behave as entry inhibitors instead. The charged nature of the chicoric acids contributes to poor cellular uptake, and these compounds are further plagued by rapid ester hydrolysis in vivo. To address these critical deficiencies, we designed neutral, nonhydrolyzable analogues of the chicoric acids. Herein, we report the synthesis, enzyme inhibition studies, and cellular antiviral data for a series of geminal disulfones. Of the 10 compounds evaluated, 8 showed moderate to high inhibition of IN in purified enzyme assays. The purified enzyme data correlated with antiviral assays for all but two compounds, suggesting alternative modes of inhibition. Time-of-addition studies were performed on these analogues, and the results indicate that they inhibit an early stage in the replication process, perhaps entry. In contrast, the most potent member of the correlative group shows behavior consistent with IN being the cellular target.
Anti-HIV Agents↗
HIV-1 integrase inhibitors: a decade of research and two drugs in clinical trial.
AIDS is currently treated with a combination therapy of reverse transcriptase and protease inhibitors. Recently, the FDA approved a drug targeting HIV-1 entry into cells. There are currently no FDA approved drugs targeting HIV-1 integrase, though many scientists and drug companies are actively in pursuit of clinically useful integrase inhibitors. The objective of this review is to provide an update on integrase inhibitors reported in the last two years, including two novel inhibitors in early clinical trials, recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors. Additionally, the proposed mechanism of diketo acid inhibition is reviewed.
Acetoacetates↗
Identification of HIV-1 integrase inhibitors via three-dimensional database searching using ASV and HIV-1 integrases as targets.
Integration of viral DNA into the host cell genome is a critical step in the life cycle of HIV. This essential reaction is catalyzed by integrase (IN) through two steps, 3'-processing and DNA strand transfer. Integrase is an attractive target for drug design because there is no known cellular analogue and integration is essential for successful replication of HIV. A computational three-dimensional (3-D) database search was used to identify novel HIV-1 integrase inhibitors. Starting from the previously identified Y3 (4-acetylamino-5-hydroxynaphthalene-2,7-disulfonic acid) binding site on the avian sarcoma virus integrase (ASV IN), a preliminary search of all compounds in the nonproprietary, open part of the National Cancer Institute 3-D database yielded a collection of 3100 compounds. A more rigorous scoring method was used to rescreen the 3100 compounds against both ASV IN and HIV-1 IN. Twenty-two of those compounds were selected for inhibition assays against HIV-1 IN. Thirteen of the 22 showed inhibitory activity against HIV-1 IN at concentrations less than 200 microM and three of them showed antiviral activities in HIV-1 infected CEM cells with effective concentrations (EC50) ranging from 0.8 to 200 microM. Analysis of the computer-generated binding modes of the active compounds to HIV-1 IN showed that simultaneous interaction with the Y3 site and the catalytic site is possible. In addition, interactions between the active compounds and the flexible loop involved in the binding of DNA by IN are indicated to occur. The structural details and the unique binding motif between the HIV-1 IN and its inhibitors identified in the present work may contribute to the future development of IN inhibitors.
Avian Sarcoma Viruses↗
HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase.
Diketo acids such as L-731,988 are potent inhibitors of HIV-1 integrase that inhibit integration and viral replication in cells. These compounds exhibit the unique ability to inhibit the strand transfer activity of integrase in the absence of an effect on 3' end processing. To understand the reasons for this distinct inhibitory profile, we developed a scintillation proximity assay that permits analysis of radiolabeled inhibitor binding and integrase function. High-affinity binding of L-731,988 is shown to require the assembly of a specific complex on the HIV-1 long terminal repeat. The interaction of L-731,988 with the complex and the efficacy of L-731, 988 in strand transfer can be abrogated by the interaction with target substrates, suggesting competition between the inhibitor and the target DNA. The L-731,988 binding site and that of the target substrate are thus distinct from that of the donor substrate and are defined by a conformation of integrase that is only adopted after assembly with the viral end. These results elucidate the basis for diketo acid inhibition of strand transfer and have implications for integrase-directed HIV-1 drug discovery efforts.
Acetoacetates↗