Article

Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design

Avexa Ltd, Richmond, Australia.
Antiviral chemistry & chemotherapy 01/2011; 21(4):155-68. DOI: 10.3851/IMP1716
Source: PubMed

ABSTRACT HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations.
A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands.
The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors.
We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold.

Download full-text

Full-text

Available from: Gregory Paul Savage, Jun 23, 2015
1 Follower
 · 
147 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV integrase became an important target for drug development more than twenty years ago. However, progress has been hampered by the lack of assays suitable for high throughput screening, a reliable crystal structure or pharmacophore. Thus, a real breakthrough was only observed in 2007 with the introduction of the first integrase inhibitor, raltegravir, into treatment. To date, the armament of integrase inhibitors is broad and covers several drugs from different classes that are under clinical trials. Among them, quinoline-based compounds and analogues occupy an important place. This review is focused on those compounds that have a quinoline scaffold and attempts to answer the question of whether quinoline is privileged for these activities. In fact, quinoline has been claimed as a privileged structure several times for different fields of activities. A closer look at its structural features may reveal the prerequisites responsible for the popularity of quinoline-based inhibitors of HIV integrase.
    Current pharmaceutical design 10/2012; DOI:10.2174/1381612811319100008 · 3.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: HIV-1 reverse transcriptase, protease and integrase have been recognized as clinically validated but still underexploited targets for antiretroviral treatment. Although a large number of inhibitors have been used in clinical trials, the rapid emergence of multiple drug-resistant strains requires the identification of not only novel classes of antiretroviral drugs that act via the unprecedented mechanism of action but also innovative drug discovery strategies towards these three important targets. This review summarizes and discusses current endeavours towards the discovery and development of novel inhibitors with alternative mechanisms of action, and also provides examples illustrating new methodologies in medicinal chemistry that contribute to the identification of novel antiretroviral agents.
    Molecular BioSystems 05/2014; 10(8). DOI:10.1039/c4mb00147h · 3.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aryl- and N-substituted isatins were converted to isa-tin-3-hydrazones and subjected to a dichlorination re-action with PhICl2. Lewis base-catalysis was key to the reaction occurring rapidly and chemoselectively, providing 3,3-dichloroindolin-2-ones in 49-99% yield, and offering a new approach to the deoxygenative di-halogenation reaction.
    Organic & Biomolecular Chemistry 11/2014; 13(3). DOI:10.1039/C4OB02213K · 3.49 Impact Factor