A New HIV Integrase Inhibitor
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Antiviral Chemistry & Chemotherapy 2009 20: 79–85 (doi: 10.3851/IMP1397) Pointer Elvitegravir: a new HIV integrase inhibitor Kazuya Shimura1 and Eiichi N Kodama1,2* 1Laboratory of Virus Control, Institute for Virus Research, Kyoto University, Kyoto, Japan 2Present address: Division of Emerging Infectious Diseases, Tohoku University School of Medicine, Sendai, Japan *Corresponding author: e-mail: [email protected] Integration is a distinctive and essential process in the inhibitor, elvitegravir, is currently showing promise in Phase HIV infection cycle and thus represents an attractive anti- III clinical studies. Once-daily administration of elvitegravir viral drug target. Integrase inhibitors combined with other has a comparable antiviral activity to twice-daily of ralte- classes of drug might contribute to long-lasting suppres- gravir in HIV-1-infected patients. Here, we highlight the sion of HIV type-1 (HIV-1) replication for many patients. Of salient features of elvitegravir: its chemical structure com- the numerous potential integrase inhibitor leads that have pared with representative integrase inhibitors, mechanism been reported, few have reached clinical trials and only of action, in vitro and in vivo activity against HIV and other one, raltegravir, has been approved (in late 2007) for the retroviruses, and the effect of integrase polymorphisms treatment of HIV-1-infected patients. Another integrase and resistance mutations on its anti-HIV activity. Introduction Combinational use of anti-HIV drugs as part of highly human genome lacks functional homologues of HIV IN active antiretroviral therapy (HAART) has opened a new [5], consequently IN is an attractive target for the devel- era in the treatment of HIV infection. With HAART, HIV opment of new anti-HIV drugs. replication has been remarkably suppressed, and reduc- Many different molecules have been reported to tion of viral load to undetectable levels and decrease of function as IN inhibitors and some of them have been HIV-associated mortality have been successfully main- evaluated for their in vivo potency in animal and human tained [1]. To date, nucleoside/nucleotide reverse tran- trials; however, until recently, no IN inhibitors were scriptase inhibitors (NRTIs), non-nucleoside/nucleotide approved in clinical use. Raltegravir (RAL; Merck) was reverse transcriptase inhibitors (NNRTIs) and protease approved for the treatment of HIV infection in Octo- inhibitors (PIs) have been widely used in HAART. How- ber 2007 [6]. RAL shows potent activity in patients ever, long-term administration of the drugs to keep viral infected with HIV type-1 (HIV-1) with resistance to replication to minimum levels unfortunately induces the other classes of drugs, including NRTIs, NNRTIs and emergence of drug-resistant variants and leads to treat- PIs [7,8]. Elvitegravir (EVG), another IN inhibitor that ment failure [2]. Moreover, some mutations can con- is currently in late Phase III clinical trials, also shows fer cross- and/or multidrug resistance to one or more potent antiviral activity in HIV-1-infected patients inhibitors in the same class of agents [3]. To cope with [9,10]. Here, we describe both in vitro and in vivo anti- this issue, in addition to discovery of new reverse tran- viral activity and resistance profiles of EVG. scriptase (RT) and protease (PR) inhibitors without cross-resistance to existing drugs, the development of Similarities and differences in chemical novel therapeutic agents targeting virus-specific mol- structures ecules remains necessary. Integrase (IN) is one of three enzymes (including PR Compounds containing diketo acids or derivatives and RT) encoded by the viral genome and, like PR and thereof, such as γ-ketone, enolizable α-ketone and car- RT, is essential for the virus replication. IN consists of boxylic acid, were postulated to be the pharmacophore three functional domains: N- and C-terminal domains, of inhibitors for retroviral IN activity. Structures of dike- and a catalytic core domain (CCD). The CCD conducts totriazole (S-1360; Figure 1), diketotetrazole (5CITEP), the intrinsic function of IN, integration, which is a diketo-carboxylic acid (L-708,906), 1,6-naphthyridine- ligation reaction between viral and host DNA [4]. The 7-carboxamide (L-870,810 and L-870,812) have been ©2009 International Medical Press 1359-6535 (print) 2040-2066 (online) 79 K Shimura & EN Kodama designed, synthesized and demonstrated to inhibit consists of three sequential steps: firstly, two nucleotides HIV-1 IN as bioisosteres of a diketo acid motif. Such located at the 3′-terminal end of the reverse transcribed bioisosteres can be replaced with similar moieties. For HIV complementary DNA are removed (3′-processing); instance, the carboxylic acid could be replaced with secondly, the processed HIV genome is integrated into not only acidic bioisosters, such as triazole and tetra- the host chromosome (strand transfer); and lastly, the zole, but also by a basic heterocycle bearing a lone-pair gap between virus and host DNA is thought to be filled donor atom, such as a pyridine ring. The heteroaromatic by host repair machinery [18]. nitrogen in the pyridine ring mimics the correspond- Using an enzymatic strand transfer assay in vitro, ing carboxyl oxygen in the diketo acid as a Lewis base EVG has an enzymatic 50% inhibitory concentra- equivalent. The enolizable ketone at the α-position of tion (IC50) value of 54 nM [14]. EVG also inhibits the diketo acids can be replaced with a phenolic hydroxyl 3′-processing reaction, but the IC50 value of EVG for group, indicating that the α-enol form of each diketo this reaction is much higher than that of strand transfer acid is its biologically active coplanar conformation. (150–300-fold) [19]. These results indicate that EVG All bioisosteres of the diketo acid motif consist of the exerts antiviral activity primarily by selective blockage three functional groups that mimic a ketone, an eno- of the strand transfer reaction. lizable ketone and a carboxyl oxygen, and can have a An in silico docking simulation of IN with EVG has coplanar conformation (Figure 1). According to availa- been performed by Savarino [20]; however, the precise ble information, we designed and synthesized a series of binding site of EVG for IN has not yet been identi- compounds that have 4-quinolone-3-carbocyclic acid, fied as cocrystallization of IN with EVG has not been including EVG [11]. The 4-quinolone-3-carbocyclic reported. Recently, Marinello et al. [19] estimated the acid has two functional groups, a β-ketone and a carbo- binding mode of EVG using an in vitro oligonucleotide- cyclic acid, which are coplanar. Therefore, a coplanar based assay. The authors postulated that EVG preferen- monoketo acid motif in 4-quinolone-3-carbocyclic acid tially inhibits the strand transfer step as EVG recognizes could work as an alternative diketo acid motif, provid- the IN–DNA complex and binds the interface between ing novel insight into new structural designs and the 3′-processed viral DNA and IN. binding mode of this type of inhibitor. RAL (Figure 1) Most IN inhibitors, including EVG and RAL, prefer- also has a structurally similar moiety, with a pyrimidi- entially block strand transfer reactions; however, there none carboxamide as a diketo acid bioisostere [12]. are several compounds that inhibit another IN-catalyz- ing reaction, 3′-processing. For example, INH-I001/ Anti-HIV activity of EVG VNIII-083, one of the recently developed IN inhibi- tors, is a conceptually new β-diketo acid derivative and EVG shows potent anti-HIV activity to various HIV inhibits 3′-processing in addition to strand transfer strains that is comparable to other IN inhibitors, such as [21,22]. It is important to keep developing IN inhibi- L-870,810 and RAL [13]. EVG suppresses replication tors that target not only strand transfer reaction, but of various HIV-1 subtypes with 50% effective concen- also 3′-processing and other steps involving in integra- tration (EC50) values in the nanomolar to subnanomo- tion, such as IN interacting molecules. lar range, including clinical isolates that have NRTI, NNRTI and/or PI resistance mutations [14]. EVG also Clinical efficacy of EVG shows antiviral activity against HIV type-2 (HIV-2), such as ROD and EHO (subtypes A and B, respectively) Anti-HIV activity of EVG in HIV-1-infected patients strains with similar EC50 values to that observed for was initially evaluated in a Phase Ib clinical trial. In HIV-1 [14]. All 14 HIV-2 clinical isolates derived from this 10-day EVG monotherapy trial, 40 HIV-1-infected IN-inhibitor-naive patients were susceptible to EVG patients were administrated one of five dosage groups with EC50 values ranging from 0.3 to 0.9 nM [15]. It as follows: 200 mg twice daily, 400 mg twice daily, has been described that the fusion inhibitor, T-20 (enfu- 800 mg twice daily, 800 mg once daily or 50 mg EVG virtide), as well as most NNRTIs, minimally suppress plus 100 mg ritonavir once daily. Ritonavir was used for replication of HIV-2 [16,17]. In contrast to these inhibi- boosting the half-life of EVG. In the 400 mg twice daily tors, EVG is substantially active against HIV-2, indicat- group, all patients showed >1 log10 copies/ml reduction ing that EVG and other IN inhibitors are ideal for the of viral load and, moreover, half of the patients expe- treatment of both HIV-1 and HIV-2. rienced a >2 log10 copies/ml decrease (Table 1) [9]. In the Phase II clinical trial, >90% patients of both groups Mechanism of action of 50 mg plus ritonavir and 125 mg plus ritonavir decreased viral load by >1 log10 copies/ml, and mean Integration is the crucial last step for the establishment CD4+ T-cell counts were increased compared with the of irreversible viral infection. The integration reaction control comparator protease inhibitor (Table 1) [10].