54 research outputs found
Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1
The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development
Economics methods in Cochrane systematic reviews of health promotion and public health related interventions.
Peer reviewedPublisher PD
High-charge 10 GeV electron acceleration in a 10 cm nanoparticle-assisted hybrid wakefield accelerator
In an electron wakefield accelerator, an intense laser pulse or charged
particle beam excites plasma waves. Under proper conditions, electrons from the
background plasma are trapped in the plasma wave and accelerated to
ultra-relativistic velocities. We present recent results from a
proof-of-principle wakefield acceleration experiment that reveal a unique
synergy between a laser-driven and particle-driven accelerator: a high-charge
laser-wakefield accelerated electron bunch can drive its own wakefield while
simultaneously drawing energy from the laser pulse via direct laser
acceleration. This process continues to accelerate electrons beyond the usual
decelerating phase of the wakefield, thus reaching much higher energies. We
find that the 10-centimeter-long nanoparticle-assisted wakefield accelerator
can generate 340 pC, 10.4+-0.6 GeV electron bunches with 3.4 GeV RMS convolved
energy spread and 0.9 mrad RMS divergence. It can also produce bunches with
lower energy, a few percent energy spread, and a higher charge. This
synergistic mechanism and the simplicity of the experimental setup represent a
step closer to compact tabletop particle accelerators suitable for applications
requiring high charge at high energies, such as free electron lasers or
radiation sources producing muon beams
Identification and Optimization of a Series of 8-Hydroxy Naphthyridines with Potent In Vitro Antileishmanial Activity:Initial SAR and Assessment of In Vivo Activity
Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition
Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis
The leishmaniases are diseases that
affect millions of people across
the world, in particular visceral leishmaniasis (VL) which is fatal
unless treated. Current standard of care for VL suffers from multiple
issues and there is a limited pipeline of new candidate drugs. As
such, there is a clear unmet medical need to identify new treatments.
This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism
of VL. The key challenges were to balance solubility and metabolic
stability while maintaining potency. Herein, strategies to address
these shortcomings and enhance efficacy are discussed, culminating
in the discovery of preclinical development candidate GSK3186899/DDD853651
(<b>1</b>) for VL
Light-triggered soft artificial muscles: Molecular-level amplification of actuation control signals
The principle of control signal amplification is found in all actuation systems, from engineered devices through to the operation of biological muscles. However, current engineering approaches require the use of hard and bulky external switches or valves, incompatible with both the properties of emerging soft artificial muscle technology and those of the bioinspired robotic systems they enable. To address this deficiency a biomimetic molecular-level approach is developed that employs light, with its excellent spatial and temporal control properties, to actuate soft, pH-responsive hydrogel artificial muscles. Although this actuation is triggered by light, it is largely powered by the resulting excitation and runaway chemical reaction of a light-sensitive acid autocatalytic solution in which the actuator is immersed. This process produces actuation strains of up to 45% and a three-fold chemical amplification of the controlling light-trigger, realising a new strategy for the creation of highly functional soft actuating systems
A laser parameter study on enhancing proton generation from microtube foil targets
The interaction of an intense laser with a solid foil target can drive [Formula: see text] TV/m electric fields, accelerating ions to MeV energies. In this study, we experimentally observe that structured targets can dramatically enhance proton acceleration in the target normal sheath acceleration regime. At the Texas Petawatt Laser facility, we compared proton acceleration from a [Formula: see text] flat Ag foil, to a fixed microtube structure 3D printed on the front side of the same foil type. A pulse length (140-450 fs) and intensity ((4-10) [Formula: see text] W/cm[Formula: see text]) study found an optimum laser configuration (140 fs, 4 [Formula: see text] W/cm[Formula: see text]), in which microtube targets increase the proton cutoff energy by 50% and the yield of highly energetic protons ([Formula: see text] MeV) by a factor of 8[Formula: see text]. When the laser intensity reaches [Formula: see text] W/cm[Formula: see text], the prepulse shutters the microtubes with an overcritical plasma, damping their performance. 2D particle-in-cell simulations are performed, with and without the preplasma profile imported, to better understand the coupling of laser energy to the microtube targets. The simulations are in qualitative agreement with the experimental results, and show that the prepulse is necessary to account for when the laser intensity is sufficiently high
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