A conserved metabolic signature associated with response to fast-acting anti-malarial agents

Characterizing the mode of action of anti-malarial compounds that emerge from high-throughput phenotypic screens is central to understanding how parasite resistance to these drugs can emerge. Here, we have employed untargeted metabolomics to inform on the mechanism of action of anti-malarial leads with different speed of kill profiles being developed by the Novartis Institute of Tropical Diseases (NITD). Time-resolved global changes in malaria parasite metabolite profiles upon drug treatment were quantified using liquid chromatography-based mass spectrometry and compared to untreated controls. Using this approach, we confirmed previously reported metabolomics profiles of the fast-killing (2.5 h) drug dihydroartemisinin (DHA) and the slower killing atovaquone. A slow-acting anti-malarial lead from NITD of imidazolopiperazine (IZP) class, GNF179, elicited little or no discernable metabolic change in malaria parasites in the same 2.5-h window of drug exposure. In contrast, fast-killing drugs, DHA and the spiroindolone (NITD246), elicited similar metabolomic profiles both in terms of kinetics and content. DHA and NITD246 induced peptide losses consistent with disruption of hemoglobin catabolism and also interfered with the pyrimidine biosynthesis pathway. Two members of the recently described class of anti-malarial agents of the 5-aryl-2-amino-imidazothiadiazole class also exhibited a fast-acting profile that featured peptide losses indicative of disrupted hemoglobin catabolism. Our screen demonstrates that structurally unrelated, fast-acting anti-malarial compounds generate similar biochemical signatures in Plasmodium pointing to a common mechanism associated with rapid parasite death. These profiles may be used to identify and possibly predict the mode of action of other fast-acting drug candidates

Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 μM) and achieves artemisinin-like kill kinetics in vitro with a parasite clearance time of \u3c24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials

Recent progress on phenotype-based discovery of dengue inhibitors

Dengue fever is the world’s most prevalent mosquito-borne viral disease caused by the four serotypes of dengue viruses, which are widely spread throughout tropical and sub-tropical countries. There has been an urgent need to identify an effective and safe dengue inhibitor as a therapeutic and a prophylactic agent for dengue fever. Most clinically approved antiviral drugs for the treatment of human immunodeficiency syndrome-1 (HIV-1) and hepatitis C virus (HCV) target virally encoded enzymes such as protease or polymerase. Inhibitors of these enzymes were typically identified by target-based screening followed by optimization via structure-based design. However, due to the lack of success to date of research efforts to identify dengue protease and polymerase inhibitors, alternative strategies for anti-dengue drug discovery need to be considered. As a complementary approach to the target-based drug discovery, phenotypic screening is a strategy often used in identification of new chemical starting points with novel mechanism of action in the area of infectious diseases such as antibiotics, antivirals, and anti-parasitic agents. This article overviews recent reports of dengue phenotypic screens, and discusses phenotype-based hit-to-lead chemistry optimizations. Challenges and outlook of dengue phenotype-based lead discovery are discussed at the end of this article

Recent progress on the discovery of non-peptidic direct renin inhibitors as antihypertensives

Introduction: The renin-angiotensin-aldosterone system (RAAS) has long been established as being a key cascade or pathway in the regulation of blood pressure and homeostasis of body fluid volume. The aspartic protease renin is responsible for the initial and rate-limiting step of the RAAS, thus inhibition of renin would favor more complete blockade of the RAAS. Therefore, direct renin inhibitors (DRIs) have been considered to be attractive agents for the treatment of hypertension. However, from the medicinal chemistry point of view, the identification of orally bioavailable, efficacious and safe low molecular weight DRIs has proven very challenging. To date, Aliskiren (Tekturna®, Rasilez®; Novartis) is the only DRI that has reached the market (FDA approved in 2007) for the treatment of hypertension. Areas covered: The present review summarizes the recent scientific accounts describing the design of new non-peptidic DRIs published from 2009-2012. Chemical structures, and preclinical DMPK properties and safety profile are collected from public scientific literatures and patent filings identified in both the Thomson Pharma and SciFinder databases. The results of early clinical trials of new candidate DRIs are also discussed. Expert opinion: The vast medicinal chemistry efforts on structure-based design of non-peptidic DRIs since the last decade have identified new chemical spaces for tight binding to renin and for gaining proper balance of physicochemical properties, potency, efficacy, and safety. However, the criteria for the selection of development candidates have become increasingly demanding, because new antihypertensives are expected to demonstrate a clear differentiation in their clinical profile, in addition to blood pressure lowering and to the benefit of the patients, as compared to established drug treatment paradigms. Hence, developing a new generation of DRIs remains a formidable task

Nucleoside inhibitors of dengue virus

Nucleoside analogs represent the largest class of antiviral agent and have been actively pursued for potential dengue virus (DENV) therapy. Here we review (i) the nucleoside analogs with known anti-DENV activities; (ii) challenges of the nucleoside antiviral approach for DENV; and (iii) potential strategies to overcome these challenges. This article forms part of a symposium on flavivirus drug discovery in Antiviral Research

Tunable two-dimensional polarization grating using a self-organized micropixelated liquid crystal structure

Utilization of the self-organizing nature of soft materials is promising for fabricating micro- and nano-structures, which can be applied for optics. Because of the high birefringence, liquid crystals are especially suitable for optoelectronic applications such as beam steering and polarization conversion. On the other hand, most self-organized patterns in liquid crystals are one-dimensional and there are only a few examples of two dimensional systems. Here we study the light diffraction from a micro-pixelated pattern of a nematic liquid crystal which is formed by self-organization of topological defects. We demonstrate that the system works as a tunable two dimensional optical grating, which splits the incident laser beam and changes the polarization property. The intensity can be controlled by electrical voltages, which cause extinction of the zeroth-order beam. The polarization properties depend on the location of spots. The numerical calculation and the theoretical analysis not only support the experimental results but also unveil the uniqueness of the pixelated structure

Synthesis of 4,6-Disubstituted Pyrimido[4,5-b]indole Ribonucleosides through Regioselective Cross-coupling Reactions

A series of new pyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 4 has been prepared by selective Pd-catalyzed cross-coupling reactions of the corresponding protected 4,6-dichloropyrimido[4,5-b]indole ribonucleoside with (het)arylboronic acids or stannanes followed by deprotection. Further cross-couplings under harsher conditions and employing X-Phos ligand proceeded at the position 6 leading to 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides. Some of these compounds displayed antiviral activity against Dengue virus