Xinyong Liu

HIV-1 NNRTIs: structural diversity, pharmacophore similarity, and implications for drug design.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent very potent and most promising anti‐AIDS agents that specifically target the HIV‐1 reverse transcriptase (RT). However, the effectiveness of NNRTI drugs can be hampered by rapid emergence of drug‐resistant viruses and severe side effects upon long‐term use. Therefore, there is an urgent need to develop novel, highly potent NNRTIs with broad spectrum antiviral activity and improved pharmacokinetic properties, and more efficient strategies that facilitate and shorten the drug discovery process would be extremely beneficial. Fortunately, the structural diversity of NNRTIs provided a wide space for novel lead discovery, and the pharmacophore similarity of NNRTIs gave valuable hints for lead discovery and optimization. More importantly, with the continued efforts in the development of computational tools and increased crystallographic information on RT/NNRTI complexes, structure‐based approaches using a combination of traditional medicinal chemistry, structural biology, and computational chemistry are being used increasingly in the design of NNRTIs. First, this review covers two decades of research and development for various NNRTI families based on their chemical scaffolds, and then describes the structural similarity of NNRTIs. We have attempted to assemble a comprehensive overview of the general approaches in NNRTI lead discovery and optimization reported in the literature during the last decade. The successful applications of medicinal chemistry strategies, crystallography, and computational tools for designing novel NNRTIs are highlighted. Future directions for research are also outlined.

Strategies for the Design of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Lessons from the Development of Seven Representative Paradigms

Transcriptase Inhibitors: Lessons from the Development of Seven Representative Paradigms Dongyue Li,† Peng Zhan,† Erik De Clercq,‡ and Xinyong Liu*,† †Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, P. R. China ‡Rega Institute for Medical Research, K.U. Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium

Recent advances in DAPYs and related analogues as HIV-1 NNRTIs.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.

Anti-HIV Drug Discovery and Development: Current Innovations and Future Trends

The early effectiveness of combinatorial antiretroviral therapy (cART) in the treatment of HIV infection has been compromised to some extent by rapid development of multidrug-resistant HIV strains, poor bioavailability, and cumulative toxicities, and so there is a need for alternative strategies of antiretroviral drug discovery and additional therapeutic agents with novel action modes or targets. From this perspective, we first review current strategies of antiretroviral drug discovery and optimization, with the aid of selected examples from the recent literature. We highlight the development of phosphate ester-based prodrugs as a means to improve the aqueous solubility of HIV inhibitors, and the introduction of the substrate envelope hypothesis as a new approach for overcoming HIV drug resistance. Finally, we discuss future directions for research, including opportunities for exploitation of novel antiretroviral targets, and the strategy of activation of latent HIV reservoirs as a means to eradicate the virus.

Design Strategies of Novel NNRTIs to Overcome Drug Resistance

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). However, to a great extent, the efficacy of NNRTI drugs is impaired by rapid emergence of drug-resistance mutations. Fortunately, detailed analysis of a wide range of crystal structures of HIV-1 RT/NNRTI complexes together with data on drug resistance mutations has identified factors important for design of inhibitors and resilience to mutations, such as, exhibiting conformational flexibility and positional adaptability of NNRTIs, forming extensive main chain hydrogen bonding, targeting highly conserved residues in HIV-1 RT and possessing unconventional mechanisms for NNRTI-mediated inhibition of RT. Besides, the plasticity of NNRTIs binding pocket (NNIBP) also provides a broad space for the discovery of new generations of NNRTIs. For instance, the composite binding pocket, integrated all available crystal structure information about the NNRTI binding site of HIV RT, was demonstrated to be an effective tool to better understand the flexible nature of the binding pocket and to identify specific inhibitors. The RT/solvent interface proved to be an attractive site for incorporating a moiety to improve water solubility and pharmacokinetics or introducing a second pharmacophore to construct multifunctional ligand. Totally, the characterization of NNRTIs and NNIBP may help in the design of more effective drugs that are potent toward wild type and drug-resistant strains of RT. In this paper we attempt to translate the general knowledge gained from a large number of related literature into a set of medicinal chemistry strategies to improve the drug resistance profile of NNRTIs.

1,2,3-Thiadiazole thioacetanilides as a novel class of potent HIV-1 non-nucleoside reverse transcriptase inhibitors

A novel series of 1,2,3-thiadiazole thioacetanilide (TTA) derivatives have been designed, synthesized and evaluated for its anti-HIV activities in MT-4 cells. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations. Among them, 2-[4-(2,4-dichlorophenyl)-1,2,3-thiadiazol-5-ylthio]-N-(2-nitrophenyl)acetamide 7d2 was identified as the most promising compound (EC(50)=0.059+/-0.02 microM, CC(50)>283.25 microM, SI>4883). The structure-activity relationship (SAR) of these novel structural congeners is discussed.

Novel 1,2,3-thiadiazole derivatives as HIV-1 NNRTIs with improved potency: Synthesis and preliminary SAR studies

A novel synthetic route and anti-HIV activity evaluation of a new series of 2-(4-(2,4-dibromophenyl)-1,2,3-thiadiazol-5-ylthio)acetamide (TTA) derivatives are described. Bioactivity assay indicated that most of the title compounds showed good activities against HIV-1. In particular, compound 7c displayed the most potent anti-HIV-1 activity (EC(50)=36.4nM), inhibiting HIV-1 replication in MT-4 cells more effectively than NVP (by sevenfold) and DLV (by eightfold). The preliminary structure-activity relationships (SAR) of the newly synthesized congeners are discussed, and molecular modeling of compound 7c in complex with HIV-1 RT is described, allowing rationalization of some SAR conclusions.

8-Hydroxyquinoline: a privileged structure with a broad-ranging pharmacological potential

Privileged structures can bind to a diverse range of targets with high affinities, thus benefiting the discovery of novel bioactive agents. 8-Hydroxyquinoline derivatives represent an important type of “privileged structure”, possessing a rich diversity of biological properties. Numerous encouraging investigations have demonstrated that this privileged structure should be further exploited for therapeutic applications in the future. In view of its predominance, and on the basis of our research interest in this scaffold, an updated and detailed account of the pharmacological properties of 8-hydroxyquinoline derivatives, as well as recent insights from structural biology, are described. Finally, some outlooks on current issues and future directions in this field of research are also provided.

Novel HIV-1 non-nucleoside reverse transcriptase inhibitors: a patent review (2005 – 2010)

Introduction: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) form the backbone of antiretroviral treatment for many HIV-infected individuals. The unique antiviral activity, high specificity and low toxicity associated with this class of agents make them a frequent choice for first-line therapy. However, the effectiveness of NNRTI drugs can be hampered by the rapid emergence of drug-resistant viruses, poor pharmacokinetic (PK) properties and severe side effects in long-term usage. Therefore, there is an urgent need to develop novel NNRTIs without such limitations. An analysis of this vast group of already existing inhibitors should constitute the basis of the effort toward the development of more potent, promising drugs or candidates. Areas covered: The present review provides an overview of NNRTI research from 2005 to 2010, and highlights some important medicinal chemistry principles and strategies in the development of NNRTIs. Expert opinion: An in-depth analysis of the common binding configuration and structural features of NNRTIs, as well as the underlying clues to the ‘follow-on’-based chemical evolution efforts (including the key medicinal chemistry principles and strategies: bioisosteric replacement, molecular hybridization, scaffold hopping, prodrug, etc.) has greatly accelerated the optimization of the pharmacodynamic (PD) and PK profiles. There is still a good deal of opportunity to discover new highly potent NNRTIs or novel scaffolds with unconventional mechanisms for reverse transcriptase (RT) inhibition.

Tetramethylpyrazine analogue CXC195 protects against cerebral ischemia/reperfusion-induced apoptosis through PI3K/Akt/GSK3β pathway in rats

CXC195 showed strongest protective effects among the ligustrazine derivatives in cells and prevented apoptosis induced by H2O2 injury. We recently demonstrated that CXC195 protected against cerebral ischemia/reperfusion (I/R) injury by its antioxidant activity. However, whether the anti-apoptotic action of CXC195 is involved in cerebral I/R injury is unknown. Here, we investigated the role of CXC195 in apoptotic processes induced by cerebral I/R and the possible signaling pathways. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2h, followed by 24h reperfusion. CXC195 was injected intraperitoneally at 2h and 12h after the onset of ischemia. The number of apoptotic cells was measured by TUNEL assay, apoptosis-related protein cleaved caspase-3, Bcl-2, Bax and the phosphorylation levels of Akt and GSK3β in ischemic penumbra were assayed by western blot. The results showed that administration of CXC195 at the doses of 3mg/kg and 10mg/kg significantly inhibited the apoptosis by decreasing the number of apoptotic cells, decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, CXC195 treatment markedly increased the phosphorylation of Akt and GSK3β. Blockade of PI3K activity by wortmannin, dramatically abolished its anti-apoptotic effect and lowered both Akt and GSK3β phosphorylation levels. Our study firstly demonstrated that CXC195 protected against cerebral I/R injury by reducing apoptosis in vivo and PI3K/Akt/GSK3β pathway involved in the anti-apoptotic effect.