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Researchers at the Crick are tackling the big questions about human health and disease, and new findings are published every week.

Our faculty have picked some of the most significant papers published by Crick scientists, all of which are freely available thanks to our open science policy.

FIKK kinase inside malaria cells

Family of parasite proteins presents new potential malaria treatment target

Researchers from the Francis Crick Institute and the Gulbenkian Institute for Molecular Medicine (GIMM) have shown that the evolution of a family of exported proteins in the malaria-causing parasite Plasmodium falciparum enabled it to infect humans. The team looked at over two thousand P. falciparum samples from people infected with malaria, finding that out of 21 FIKK kinases, 18 were protected against harmful mutations, suggesting they are necessary for the parasite to infect humans and likely helped it evolve. The researchers then expressed the FIKK kinases in bacteria to see what each one does. This experiment showed that the FIKK kinases all had different protein targets in the cell. Finally, the team showed that the specificity of FIKK kinases is linked to small changes in a flexible loop region, and that two molecules could block most FIKK kinases in a test tube. Blocking all FIKK kinases could be a promising treatment strategy for malaria.

The fast-evolving FIKK kinase family of Plasmodium falciparum can be inhibited by a single compound

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Published in Nature Microbiology

Published

PADI4 enzyme

A RaPID way to discover covalent inhibitors

Covalent drugs - which bind irreversibly to their targets - have increased potency and reduce the frequency a dose must be taken. However, it's challenging to design peptide inhibitors for enzymes, let alone to further alter them to contain a reactive group which will form a covalent bond to the enzyme. Researchers at the Crick used a specialised screening system called RaPID to identify irreversible, high affinity binders for a target of interest. This enabled them to go from a library of 1 trillion peptides down to an enriched library of peptides that tightly bind to a protein target. They incorporated unnatural amino acids with an irreversibly-binding 'warhead' into the peptide library, which enabled covalent binding to the target. The new system was used to identify several covalent peptides which tightly bind to the protein target PADI4, which is misregulated in rheumatoid arthritis, lupus and several cancers. These peptides, which also inhibit PADI4 activity, could form the basis of drugs for these diseases.

Discovering covalent cyclic peptide inhibitors of peptidyl arginine deiminase 4 (PADI4) using mRNA-display with a genetically encoded electrophilic warhead

Published in Communications Chemistry

Published

PADI4 enzyme

A peptide toolkit to study PADI4 enzyme, which is dysregulated in disease

Dysregulation of an enzyme called peptidyl arginine deiminase IV (PADI4) has been linked to many diseases including various cancers and atherosclerosis. However, little is known about its regulation within cells, largely due to al ack of appropriate chemical tools. In this study researchers at the Crick used the RaPID system, a very powerful screening technology, to identify binders of PADI4 from DNA-encoded libraries of more than a trillion cyclic peptides. We developed these binders into three novel cyclic peptide chemical tools that modulate PADI4 activity: one to target the active conformation of PADI4, one to bind to the allosteric site and activate PADI4, and a third to use as a tool to identify different PADI4 protein binding partners that may regulate its activity. Together these peptides provide a new toolkit for the study of PADI4 in the context of health and disease.

A cyclic peptide toolkit reveals mechanistic principles of peptidylarginine deiminase IV regulation

Published in Nature Communications

Published

Image illustrates molecules being screened as potential drugs

Boosting drug discovery of cyclic peptides for previously undruggable targets

Cyclic peptides are an exciting new drug modality that can be used against disease targets that have been impossible to treat with traditional small molecule drugs. However, despite their promise, it can still be difficult to develop peptides for many important drug targets due to challenges with making the target protein for drug screening. To address this, researchers at the Crick have developed and applied a new method to discover cyclic peptides without the need for making the target by performing the screening process directly in the target’s native cellular environment. In the future this will allow cyclic peptide drug discovery against a wide range of previously undruggable targets.

mRNA display in cell lysates enables identification of cyclic peptides targeting the BRD3 extraterminal domain

Published in Angewandte Chemie International Edition

Published

Multiciliated cells in airways

Genetic control of cilia coordination in airways could help to understand COPD

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease, estimated to be the third biggest killer worldwide (WHO). Researchers at the Crick investigated a gene associated with COPD risk called FAM13A. They found that FAM13A exists in short and long forms in humans and that only the longer form can act as an enzyme in specialised ‘multiciliated’ cells in the airway. These cells contain projections called cilia whose coordinated beating moves mucus out of the lungs. By genetically removing the long form of FAM13A in human cell cultures that resemble the air-exposed lining of airways, the team showed that FAM13A is necessary for coordinating cilia movement. In an additional experimental model for multiciliated cells, they reduced Fam13a expression in Xenopus (frog) embryos, which also led to defects in cilia activity. This research could inform why mutations in the FAM13A gene are linked to COPD in humans.

The FAM13A long isoform regulates cilia movement and
coordination in airway mucociliary transport

Published in American Journal of Respiratory Cell and Molecular Biology

Published

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Research case studies 

Explore a selection of recent case studies that spotlight particular areas of research at the Crick.