br Drugs approved or in development To

Drugs approved or in development To date, three drugs: RAL (MK-0518), EVG (GS-9137) and DTG (GSK1349572) [104], have been approved by the FDA. Their structures are shown in Fig. 5. DTG is under development by GlaxoSmithKline (GSK), and studies have shown DTG to be effective in patients with resistance to the IN inhibitor RAL. In contrast to EVG, DTG does not require boosting with an additional drug [105]. Unfortunately, resistance to these new medicines (RAL and EVG) has been reported recently [106]. Three amino Fenoprofen Calcium residues: Gln148, Asn155 and Tyr143, were important for RAL to interact with HIV-1 IN, and mutations of them were common pathways for RAL or EVG resistance [106]. Therefore, it is crucial to develop the next generation of HIV-1 IN inhibitors. Clinical trials are essential stages before a drug is approved for the market. Some candidates passed these stages successfully becoming drugs, whereas others failed in these stages because of poor curative effect, low bioavailability, toxicity or other effects. S/GSK1265744 is an investigational drug in Phase IIb clinical trials that is being studied for the treatment of HIV infection as an HIV-1 INSTI [107]. It has a structure similar to DTG, and it does not require boosting with an additional drug either [107]. In a Phase I/II study, different strengths of unboosted S/GSK1265744 taken orally were compared with a placebo in healthy participants and HIV-infected participants. In HIV-infected adults, S/GSK1265744 was effective in reducing viral load. In terms of safety, S/GSK1265744 was well tolerated and most side-effects were considered to be mild. The most common side-effect that occurred was headache [108]. A Phase I study of healthy adults taking a long-acting formulation of S/GSK1265744 given by injection has been completed. This study indicated that long-acting injectable formulations of S/GSK1265744 could be an effective delivery method, with the potential for achieving substantial antiviral activity by using monthly or quarterly dosing. In this study, the most common side-effect was temporary, mild-to-moderate injection site reactions, such as skin redness, irritation or bumps. More studies are needed to determine the safety and efficacy of S/GSK1265744 [109].
Concluding remarks
Acknowledgements This work was supported by the National Natural Science Foundation of China (21375007) and the ‘Chemical Grid Project’ of Beijing University of Chemical Technology. We thank the comments from Dr. J. Kirchmair, L. Tan and J. Gasteiger.
Introduction During HIV-1 replication, the viral RNA genome is reverse transcribed into double stranded DNA by HIV-1 reverse transcriptase (RT) and this DNA is subsequently integrated into the host genome by the HIV-1 integrase (IN). HIV-1 IN is composed of three functional domains: the N-terminal region, the catalytic core domain (containing the active site) and the C-terminal region. IN carries out integration of viral DNA into the host chromosome through a series of consecutive steps. First, the HIV-1 IN multimer binds to a short sequence located at either end of the long terminal repeat (LTR) of the viral DNA and specifically cleaves a dinucleotide from each of the 3′ ends of the LTR, a process known as 3′-processing. IN-viral DNA complexes are subsequently translocated to the nucleus, where IN integrates the processed viral DNA into the host genome with the help of certain cellular co-factors (a step referred to as strand transfer) (Pommier et al., 2005, Krishnan and Engelman, 2012). Since IN is an essential enzyme in the viral life cycle without a homologue in human cells, IN is an attractive and validated therapeutic target for the development of anti-HIV drugs (Hazuda, 2012). And, indeed, the multistep process of the integration reaction permits several potential sites within IN to be targeted: i.e. IN binding to the viral DNA, the 3′ processing step, the strand transfer step, IN multimerization, and the interaction of IN with cellular co-factors (Voet et al., 2009, Al-Mawsawi and Neamati, 2011).