Studies on HIV-1 DNA integration / Nick Vandegraaff.

"February, 2002"Includes bibliographical references (leaves 156-182)xiv, 182, [26] leaves : ill. (some col.) ; 30 cm.Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 200

Bioactive glycosides from the African medicinal plant Boerhavia erecta L.

Phytochemical studies of the previously unexplored stem of Boerhavia erecta from Burkina Faso, resulted in the isolation of an unreported glycoside 4, 2,3-dihydroxypropylbenzoate-3-O-β-[4″-methoxy] glucuronide as well as seven known glycosides (1-3, 5-8). The major isolate 5 and 8 indicated a significant inhibition against HIV integrase (IC50 10 and 22 μg/mL, respectively). The extracts and isolates were also tested for anti-malarial activity, but insignificant activity was observed

The discovery of allyltyrosine based tripeptides as selective inhibitors of the HIV-1 integrase strand-transfer reaction

From library screening of synthetic antimicrobial peptides, an O-allyltyrosine-based tripeptide was identified to possess inhibitory activity against HIV-1 integrase (IN) exhibiting an IC50 value of 17.5 μM in a combination 3′-processing and strand transfer microtitre plate assay. The tripeptide was subjected to structure-activity relationship (SAR) studies with 28 peptides, incorporating an array of natural and non-natural amino acids. Resulting SAR analysis revealed the allyltyrosine residue was a key feature for IN inhibitory activity whilst incorporation of a lysine residue and extended hydrophilic chains bearing a terminal methyl ester was advantageous. Addition of hydrophobic aromatic moieties to the N-terminal of the scaffold afforded compounds with improved inhibitory activity. Consolidation of these functionalities lead to the development of the tripeptide 96 which specifically inhibited the IN strand-transfer reaction with an IC50 value of 2.5 μM

Bioactive glycosides from the African medicinal plant <i>Boerhavia erecta</i> L.

<div><p>Phytochemical studies of the previously unexplored stem of <i>Boerhavia erecta</i> from Burkina Faso, resulted in the isolation of an unreported glycoside <b>4</b>, 2,3-dihydroxypropylbenzoate-3-<i>O</i>-β-[4″-methoxy] glucuronide as well as seven known glycosides (<b>1</b>–<b>3</b>, <b>5</b>–<b>8</b>). The major isolate <b>5</b> and <b>8</b> indicated a significant inhibition against HIV integrase (IC₅₀ 10 and 22 μg/mL, respectively). The extracts and isolates were also tested for anti-malarial activity, but insignificant activity was observed.</p></div

A structure-based design approach to advance the allyltyrosine-based series of HIV integrase inhibitors

As of mid-2017, only one structure of the human immunodeficiency virus (HIV) integrase core domain co-crystallised with an active site inhibitor was reported. In this structure (1QS4), integrase is complexed with a diketo-acid based strand-transfer inhibitor (INSTI). This structure has been a preferred platform for the structure-based design of INSTIs despite concerns relating to structural irregularities arising from crystallographic packing effects. A survey of the current pool of 297 reported integrase catalytic core structures indicated that the anatomy of the active site in the complex structure 1QS4 exhibits subtle variations relative to all other structures examined. Consequently, the 1QS4 structure was employed for docking studies. From the docking of twenty-seven allyltyrosine analogues, a 3-point inhibitor binding motif required for activity was established and successfully utilised in the development of a tripeptide displaying an EC50 value of 10 ± 5 μM in HIV infected human T-cells. Additional docking of in-house compound libraries unearthed a methyl ester based nitrile derivative displaying an IC50 value of 0.5 μM in a combined 3\u27-processing and strand-transfer assay

A structure-based design approach to advance the allyltyrosine-based series of HIV integrase inhibitors

As of mid-2017, only one structure of the human immunodeficiency virus (HIV) integrase core domain co-crystallised with an active site inhibitor was reported. In this structure (1QS4), integrase is complexed with a diketo-acid based strand-transfer inhibitor (INSTI). This structure has been a preferred platform for the structure-based design of INSTIs despite concerns relating to structural irregularities arising from crystallographic packing effects. A survey of the current pool of 297 reported integrase catalytic core structures indicated that the anatomy of the active site in the complex structure 1QS4 exhibits subtle variations relative to all other structures examined. Consequently, the 1QS4 structure was employed for docking studies. From the docking of twenty-seven allyltyrosine analogues, a 3-point inhibitor binding motif required for activity was established and successfully utilised in the development of a tripeptide displaying an EC50 value of 10 +/- 5 mu M in HIV infected human T-cells. Additional docking of "in-house" compound libraries unearthed a methyl ester based nitrite derivative displaying an IC50 value of 0.5 mu M in a combined 3'-processing and strand-transfer assay