Modeling of the Inhibition of Retroviral Integrases by Styrylquinoline Derivatives

Ouali, Mohammed Assam; Laboulais, Cyril; Leh, Hervé; Gill, D M; Desmaële, Didier; Mekouar, Khalid; Zouhiri, Fatima; d’Angelo, Jean; Auclair, Christian; Mouscadet, Jean François; Bret, Marc Le

doi:10.1021/jm9911581

Cited by 63 publications

(49 citation statements)

References 43 publications

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“…A fluorescence study of SQ in the absence or in the presence of IN was carried out to get experimental support of the existence of IN-SQ complexes. As found previously (Ouali et al, 2000;Zouhiri et al, 2000) and confirmed in this study (see below), the in vitro inhibition properties of SQ derivatives originate in the simultaneous presence of both C7-COOH and C8-OH groups in the quinoline subunit and are less sensitive to modifications at the C3Ј or C4Ј positions. Accordingly, KHD161 and FZ55 are characterized by very similar inhibition properties.…”

Section: Docking Of Khd161 To the Catalytic Core Domain Of Insupporting

confidence: 89%

“…The structure of the drug KHD161 was optimized as described previously (Ouali et al, 2000) and the tautomeric form with the 7-COO Ϫ and 8-OH groups was used. The drug was rotated by 12°increments and for each of these 12,660 orientations, the translations giving the best overlap were stored when the electrostatic drug-target interaction energy was favorable.…”

Section: Dockingmentioning

confidence: 99%

“…The drug was rotated by 12°increments and for each of these 12,660 orientations, the translations giving the best overlap were stored when the electrostatic drug-target interaction energy was favorable. As described previously (Ouali et al, 2000), the best 1000 overlapping complexes and the most favorable 200 complexes for the pure electrostatic interaction were minimized, with both drug and target being optimized. During the minimization, the aqueous medium was implicitly represented through a sigmoidal distance-dependent dielectric constant (Lavery et al, 1986).…”

Section: Dockingmentioning

confidence: 99%

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Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Deprez¹,

Barbe²,

Kolaski³

et al. 2004

Mol Pharmacol

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Styrylquinoline derivatives (SQ) efficiently inhibit the 3Ј-processing activity of integrase (IN) with IC 50 values of between 0.5 and 5 M. We studied the mechanism of action of these compounds in vitro. First, we used steady-state fluorescence anisotropy to assay the effects of the SQ derivatives on the formation of IN-viral DNA complexes independently of the catalytic process. The IC 50 values obtained in activity and DNAbinding tests were similar, suggesting that the inhibition of 3Ј-processing can be fully explained by the prevention of IN-DNA recognition. SQ compounds act in a competitive manner, with K i values of between 400 and 900 nM. In contrast, SQs did not inhibit 3Ј-processing when IN-DNA complexes were preassembled. Computational docking followed or not by molecular dynamics using the catalytic core of HIV-1 IN suggested a competitive inhibition mechanism, which is consistent with our previous data obtained with the corresponding Rous sarcoma virus domain. Second, we used preassembled IN-preprocessed DNA complexes to assay the potency of SQs against the strand transfer reaction, independently of 3Ј-processing. Inhibition occurred even if the efficiency was decreased by about 5-to 10-fold. Our results suggest that two inhibitorbinding modes exist: the first one prevents the binding of the viral DNA and then the two subsequent reactions (i.e., 3Ј-processing and strand transfer), whereas the second one prevents the binding of target DNA, thus inhibiting strand transfer. SQ derivatives have a higher affinity for the first site, in contrast to that observed for the diketo acids, which preferentially bind to the second one.Integration of the HIV-1 DNA into the host genome ensures stable maintenance of the viral genome and perpetuation of the virus in the host organism. Therefore, this reaction, catalyzed by integrase (IN), is a key process in the life cycle of the virus. Inhibitors of therapeutic interest for AIDS exist. Inhibitors that act early in the replication cycle target reverse transcriptase and those that act later target protease. The high mutation rate of HIV means that drug resistance is emerging, making it necessary to develop new drugs with different targets (combined therapies). Thus, it is essential to find drugs that target alternative steps of the HIV-1 replication cycle. IN, the third enzyme of the Pol precursor protein, is then an attractive target for novel drugs because of its central role in the HIV-1 life cycle.IN is a 32-kDa protein (288 amino acids) that consists of three functional domains. The central domain (or core domain, residues 50 -210) contains the catalytic triad (DDE) that is essential for enzymatic activity. This domain is flanked by the N-terminal domain (which has a role in the assembly of an active multimeric form of the enzyme) and the C-terminal domain (which has a role in the nonspecific DNAbinding activity). These three domains, protein oligomerization, the integrity of the catalytic triad, and a cationic cofactor such as magnesium are all necessary fo...

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Section: Docking Of Khd161 To the Catalytic Core Domain Of Insupporting

confidence: 89%

Section: Dockingmentioning

confidence: 99%

Section: Dockingmentioning

confidence: 99%

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Mechanism of HIV-1 Integrase Inhibition by Styrylquinoline Derivatives in Vitro

Deprez¹,

Barbe²,

Kolaski³

et al. 2004

Mol Pharmacol

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“…They corresponded to KH161, KH211, FZ41, FZ149, KH227, FZ123, and FZ55. Their effects on HIV-1 IN have been described previously (5,10,13,20,33,40,41). The two DKAs, a kind gift from Merck, were L-731,988 and L-839,616.…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of Strand Transfer That Prevent Integration and Inhibit Human T-Cell Leukemia Virus Type 1 Early Replication

Rabaaoui

Zouhiri²,

Lançon

et al. 2008

Antimicrob Agents Chemother

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The replication of the retrovirus human T-cell leukemia virus type 1 (HTLV-1) is linked to the development of lymphoid malignancies and inflammatory diseases. Data from in vitro, ex vivo, and in vivo studies have revealed that no specific treatment can prevent or block HTLV-1 replication and therefore that there is no therapy for the prevention and/or treatment of HTLV-1-associated diseases in infected individuals. HTLV-1 and human immunodeficiency virus type 1 (HIV-1) integrases, the enzymes that specifically catalyze the integration of these retroviruses in host cell DNA, share important structural properties, suggesting that compounds that inhibit HIV-1 integration could also inhibit HTLV-1 integration. We developed quantitative assays to test, in vitro and ex vivo, the efficiencies of styrylquinolines and diketo acids, the two main classes of HIV-1 integrase inhibitors. The compounds were tested in vitro in an HTLV-1 strand-transfer reaction and ex vivo by infection of fresh peripheral blood lymphocytes with lethally irradiated HTLV-1-positive cells. In vitro, four styrylquinoline compounds and two diketo acid compounds significantly inhibited HTLV-1 integration in a dose-dependent manner. All compounds active in vitro decreased cell proliferation ex vivo, although at low concentrations; they also dramatically decreased both normalized proviral loads and the number of integration events during experimental ex vivo primary infection. Accordingly, diketo acids and styrylquinolines are the first drugs that produce a specific negative effect on HTLV-1 replication in vitro and ex vivo, suggesting their potential efficiency for the prevention and treatment of HTLV-1-associated diseases.Human T-cell leukemia virus type 1 (HTLV-1) and human immunodeficiency virus type 1 (HIV-1) are exogenous retroviruses pathogenic for humans. Although both viruses are lymphotropic, their pathogenicities depend on strongly distinct mechanisms. Schematically, in vivo, HIV infection triggers the progressive elimination of CD4 ϩ lymphocytes, leading to immunosuppression, whereas HTLV-1 infection is associated with the clonal expansion of infected cells, possibly leading to malignant CD4 ϩ proliferation or to spinal cord infiltration, infection, and inflammation. Clinically, HIV-induced cellular defects are regularly linked to the development of AIDS, whereas in a minority of carriers, HTLV-1 infection causes adult T-cell leukemia/lymphoma (ATLL) and/or tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). The median length of survival for patients with AIDS receiving modern treatment, i.e., triple therapy, is currently over 8 years; in contrast, the prognosis for HTLV-1-associated diseases remains extremely poor. To date, there is no effective treatment for TSP/HAM (32), while the median overall length of survival for patients with ATLL does not exceed a few months (3).Integration of a DNA copy of the viral RNA genome into host cellular DNA is essential and unique to the retroviral life cycle. After completion of reverse...

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“…A number of metal chelates, as agent for mediation of strand scission of duplex DNA and as chemotherapeutic agents, have been used as probes of DNA structure in solution (4,5) . In medicine particularly , a new class of drugs have been reported as potent HIV-1 inhibitors (6,7) , protein tyrosine kinase inhibitors (8) , protozoal -retroviral co-infections (9) , anti HIV-1 agent (10) and therapeutic drugs for the inflammatory diseases (11) . Looking to the above important of DNA binding study of ligands and metal complexes (12,13) , the present paper describes mixed ligand synthesis and DNA binding interaction assay of L1 and L2.…”

Section: Introductionmentioning

confidence: 99%