Science Pool

Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK

As part of our ongoing efforts at Evotec to tackle AMR through the design of novel antibiotics we have been working with Boston-based X-Biotix in a collaboration focussed on targeting priority Gram-negative pathogens. We are now able to share the story of our work on inhibitors of UDP-N-Acetylglucosamine Acyltransferase (LpxA), a key enzyme in the biosynthetic pathway of the outer membrane lipopolysaccharide of Gram-negative bacteria. Building on hit-finding work at X-Biotix we put together a multi-disciplinary team including Medicinal Chemistry, Computational Chemistry, Structural Biology and DMPK at our Abingdon UK site, in vitro and in vivo Microbiology and PK at our Alderley Park UK site, and in vitro Biology at our site in Hamburg, Germany. Through structure and property-based optimisation we were able to design highly potent inhibitors of Pseudomonas aeruginosa LpxA that were active against multi-drug resistant clinical isolates. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa bacteria. In our paper in the Journal of Medicinal Chemistry we share the optimisation story, along with a significant quantity of activity data that we hope will be useful for other teams working on small molecule strategies to tackle P. aeruginosa and other Gram-negative bacteria.

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Arthralgia (persistent pain or stiffness of the joints) is a common symptom of chikungunya virus infection which can persist for many months following the disease. This condition is associated with significant disability and reduced quality of life. In order to manage individual clinical expectations and long term burden on the population following a chikungunya virus infection epidemic, it is critical to know the expected duration of the post infection arthralgia. 

In this publication, we focus on:

• a background to chikungunya virus and its symptoms including arthralgia
• a literature review of published cohort studies which have tracked the symptoms of chikungunya virus over time after infection with the virus
• using simple statistical models to estimate the average arthralgia resolution rate

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Following chikungunya virus infection, chronic rheumatological symptoms are similar to those observed with rheumatoid arthritis. To further evaluate this, a comparison was made between the relevance of joint counts and symptoms between the two conditions.

In this publication, we focus on:

• a background to chikungunya virus and its various symptoms including chronic joint pain and inflammation
• a cross sectional study of 40 patients with chronic chikungunya arthralgia and 40 patients with rheumatoid arthritis in order to compare symptoms
• an assessment of the relevance of joint counts in both conditions and their relationship with disability

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Mutant huntingtin (mHTT) protein has been implicated in neuronal degeneration in Huntington's Disease.

In this publication, we focus on:

• a background to the inherited neurodegenerative disorder, Huntington's Disease, including the impact of the mutant huntingtin (mHTT) gene
• a discussion of the use of positron emission tomography (PET) to monitor disease progression
• the identification of a novel ligand CHDI-626 which binds to mHTT aggregates

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Mutant huntingtin (mHTT) forms protein aggregates characteristic of Huntington's Disease pathology.

In this publication, we focus on:

• a background to Huntington's Disease including the mutant huntingtin gene (mHTT)
• a discussion of the benefits of sensitive biomarkers to monitor disease progression
• the discovery of an mHTT aggregate-specific PET ligand suitable for live brain imaging

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Huntington's Disease is caused a mutation in the huntingtin (mHTT) gene which codes for the huntingtin (HTT) protein.

In this publication, we focus on:

• a background to link between Huntington's Disease and the mutant huntingtin gene (mHTT)
• the development of PET tracers for imaging mHTT aggregates
• characterisation of these PET tracers including pharmacological investigation of their binding affinities and selectivity

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The ‘core’ metabolome of the Bacteroidetes genus Chitinophaga was recently discovered to consist of only seven metabolites. A structural relationship in terms of shared lipid moieties among four of them was postulated. Here, structure elucidation and characterization via ultra-high resolution mass spectrometry (UHR-MS) and nuclear magnetic resonance (NMR) spectroscopy of those four lipids (two lipoamino acids (LAAs), two lysophosphatidylethanolamines (LPEs)), as well as several other undescribed LAAs and N-acyl amino acids (NAAAs), identified during isolation were carried out. 

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The need for antimalarial drugs is urgent in the face of growing resistance to existing therapies. Murithi et al. characterized MMV688533, an acylguanidine identified from compounds inhibiting known human drug targets that were screened for activity against Plasmodium falciparum

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