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. 2012:2012:863405.
doi: 10.1155/2012/863405. Epub 2012 Aug 7.

Cellular cofactors of lentiviral integrase: from target validation to drug discovery

Oliver Taltynov  1 , Belete A Desimmie, Jonas Demeulemeester, Frauke Christ, Zeger Debyser
Affiliations

Cellular cofactors of lentiviral integrase: from target validation to drug discovery

Oliver Taltynov et al. Mol Biol Int. 2012.

Abstract

To accomplish their life cycle, lentiviruses make use of host proteins, the so-called cellular cofactors. Interactions between host cell and viral proteins during early stages of lentiviral infection provide attractive new antiviral targets. The insertion of lentiviral cDNA in a host cell chromosome is a step of no return in the replication cycle, after which the host cell becomes a permanent carrier of the viral genome and a producer of lentiviral progeny. Integration is carried out by integrase (IN), an enzyme playing also an important role during nuclear import. Plenty of cellular cofactors of HIV-1 IN have been proposed. To date, the lens epithelium-derived growth factor (LEDGF/p75) is the best studied cofactor of HIV-1 IN. Moreover, small molecules that block the LEDGF/p75-IN interaction have recently been developed for the treatment of HIV infection. The nuclear import factor transportin-SR2 (TRN-SR2) has been proposed as another interactor of HIV IN-mediating nuclear import of the virus. Using both proteins as examples, we will describe approaches to be taken to identify and validate novel cofactors as new antiviral targets. Finally, we will highlight recent advances in the design and the development of small-molecule inhibitors binding to the LEDGF/p75-binding pocket in IN (LEDGINs).

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Figures

Figure 1
Figure 1
Domain organization of HIV-1 IN and LEDGF/p75. (a) HIV-1 IN is composed of an N-terminal domain (NTD), a catalytic core domain (CCD), and a C-terminal domain (CTD). The CCD contains the catalytically essential DD(35)E motif and the hot spots for interaction with the IBD in LEDGF/p75. The Asp and Glu residues of the CCD coordinate one or two Mg2+ ions and are involved in 3′ processing and DNA strand-transfer activities. (b) LEDGF/p75 has several structural motifs involved in chromatin tethering and protein-protein interactions. The PWWP domain, the charged regions (CRs), and AT-hooks are involved in chromatin binding. The C-terminus contains the well-characterized IN binding domain (IBD) and acts as a protein interaction playground. Asp residue 366 critical for HIV-1 IN binding is indicated.
Figure 2
Figure 2
Algorithm to identify and validate novel cofactors as antiviral targets with examples of candidate and validated HIV-1 IN cellular cofactors at particular stages of validation. The algorithm was used in the validation of LEDGF/p75 and TRN-SR2 as cellular cofactors of HIV-1 IN and in validating LEDGF/p75 as an antiviral target. In case of some candidate cofactors, the experimental intervention verifying affect on HIV replication was accompanied by toxicity. These candidates were excluded from follow-up steps of drug target validation.These proteins can still beinvolved in the HIV life cycle but were not considered priority targets.
Figure 3
Figure 3
Chemical structures of the LEDGINs. Of the 25 molecules tested in AlphaScreen, compound 1 was identified as the initial hit with in vitro activity. Compounds 2 and 3 are commercial congeners of 1. Compounds 4–7 are newly synthesized compounds with improved in vitro and in vivo activities. After serial rounds of optimization by medicinal chemistry, the early lead compounds 6 and 7 were identified with potent and selective anti-HIV activity. Compound 7 has submicromolar antiviral activity [37].
Figure 4
Figure 4
Cartoon representation of the LEDGIN 3 (yellow) superimposed with the LEDGF/p75 IBD (gray) in the pocket at the interface of the IN CCD dimer (light blue and orange). LEDGINs bind to the LEDGF/p75 binding pocket in HIV-1 IN and thereby block the interaction of the IBD of LEDGF/p75 with the dimer of the CCD, thereby interfering with tethering of the HIV-1 PIC to the host cell chromatin.
Figure 5
Figure 5
Scheme of nuclear import of the PIC and TRN-SR2 recycling.
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