Taking away the energy from T cell proliferation

A new class of immunosuppressive compounds is shown to block T lymphocyte proliferation - the process by which white blood cells are activated during an immune response - by inhibiting lactate transport, as reported in the December issue of Nature Chemical Biology.

Proliferating T cells rely on energy from aerobic glycolysis, a process which generates ATP through the conversion of glucose to pyruvate or lactate. Clare Murray and colleagues have found that the immunosuppressive molecules function by inhibiting monocarboxylate transporter 1 (MCT1), a membrane protein involved in pumping lactate out of cells. Forcing intracellular lactate accumulation reduces the levels of glycolysis sufficiently to sap the energy required for rapid cellular growth, say the team.

Starting with compounds that showed potent inhibition of T cell proliferation in vitro and effective immunosuppression in vivo, Murray used proteomic methods to identify the target protein as MCT1. Consistent with MCT1 being the functional target, proliferating T cells had higher levels of MCT1 than resting cells did. These increased protein levels corresponded with increased lactate transport, which could be blocked by the inhibitory compounds, resulting in intracellular lactate accumulation and reduced glycolysis.

In addition to identifying a promising new target for developing immunosuppressants, these compounds will now provide a new tool for understanding MCT1 biology and the role of glycolysis in cell proliferation.

Agonizing over CD40

A new approach to targeting cellular receptors in the immune system using small molecules is reported in the December issue of Nature Chemical Biology. Gilles Guichard and colleagues designed a molecular scaffold that presents short peptide sequences that bind to and activate cellular receptors. These molecules offer an attractive model for cancer immunotherapy and boosting immune responses to infections.

Tumor necrosis factor (TNF) proteins are a family of cytokine proteins that regulate the functions of immune cells. TNF proteins assemble into bundles of three – or trimeric bundles – and bind to TNF receptors, which 'read' cytokine signals on the surface of immune cells. The team set out to create small molecules that could mimic the cytokine properties of trimeric CD40 ligand (CD40L), which exerts its effects by binding to trimeric CD40 receptors. The authors synthesized a circular 'core' peptide with three appendages, at twelve, four and eight o’clock. To each appendage, they attached a short peptide derived from CD40L that is known to interact with CD40. They showed that these trimeric molecules act as mimics of CD40L by binding to CD40 on cells and activating downstream signaling pathways. In addition, the molecules targeted only CD40 and did not activate other TNF receptor proteins. This specificity suggests that these molecular 'cores' may be a versatile platform for targeting different TNF receptors by decorating them with different TNF peptide fragments.

These molecules suggest new strategies for cancer immunotherapy and activation of immune systems during infection.

Can drug side effects be predicted?

A paper in the December issue of Nature Chemical Biology reports a method for correlating a drug's biochemical activity with its clinical side effects. During clinical trials, drug candidates have a high failure rate, which results in part from unexpected toxicities. A method for predicting these unwanted side effects could prove important for choosing the right drug candidates to enter into clinical trials.

Robert Volkmann and Anton Fliri and colleagues hypothesized that the biochemical activities of chemical compounds could be used to predict side effects. To test this idea, the authors looked at the biochemical activity of a drug in inhibiting a large panel of proteins. This resulted in a 'fingerprint' of the compound's biochemical activity. They then looked at the side effects induced by the same drug during clinical trials, which led to a fingerprint of the compound's side effects. By comparing the biochemical and side effect fingerprints for 1,045 drugs, the authors found that there was a significant correlation between a drug's biochemical activity in vitro and the clinical side effects it induced.

This result suggests that it will eventually be possible to predict the expected side effects of a new drug candidate by analyzing its biochemical activity fingerprint, which would significantly improve the success rate of drug development.

Skeletons in cancer’s closet

Scientists have found the mechanism of action of a natural product known to be toxic to cancer cells. The research, reported in the December issue of Nature Chemical Biology, shows that a toxin called bistramide A prevents cells from dividing properly by targeting their actin cytoskeleton.

Sea squirts (Lissoclinum bistratum) are invertebrate marine animals that produce bistramides as a by-product of metabolism. Bistramide A has various toxic effects on the cells of mammals ranging from frogs to humans. To determine the mechanism of this toxicity, Sergey Kozmin and colleagues looked at the contractile ring of cells, a bundle of actin polymers that provide the mechanical force to pinch cells apart during cell division. They found that by binding to actin, bistramide A prevented cells from splitting apart during division. By blocking cell division, bistramide A blocks the multiplication of cells.

Besides increasing our knowledge of the toxic metabolite, this research suggests a way to block cell division in rapidly multiplying cancer cells.

Small-molecule suppressor

A paper in the December issue of Nature Chemical Biology reports a small molecule that suppresses the phenotype of a zebrafish mutation. Zebrafish are an increasingly popular model organism because they can be readily manipulated genetically and grow very quickly, allowing rapid in vivo analysis of mutation phenotypes.

Zebrafish have proven amenable to whole-organism chemical screening. Genes involved in the cell-cycle are very similar in zebrafish and humans, making zebrafish an easy system for studying genes affecting cell division, a process which is often compromised in cancer. Leonard Zon and colleagues have combined the power of genetics and chemical screening to identify a chemical suppressor of a specific cell-cycle mutation.

In a previous publication, the authors identified a zebrafish mutation called crash&burn (crb) that results in decreased expression of the key cell-cycle regulator cyclin B1 and causes mitotic arrest and genome instability. The team have now conducted a large-scale chemical screen and identified a compound, persynthamide, which suppresses the crb phenotype. The small molecule was shown to act by delaying progression through S phase of the cell cycle, the time when DNA is replicated before cell division. However, the precise molecular target of the small molecule remains to be identified.

In addition to providing a valuable new lead for a mitotic modulator, the use of zebrafish to identify a cell-cycle regulator raises the possibility of using transgenic zebrafish to screen directly for chemical suppressors of cancers that arise from cell-cycle defects.

Monocarboxylate transporter MCT1 is a target for immunosuppression

Clare M Murray, Raymond Hutchinson, John R Bantick, Graham P Belfield, Amanda D Benjamin, Diana Brazma, Robert V Bundick, I David Cook, Robert I Craggs, Susan Edwards, Leslie R Evans, Richard Harrison, Elain Holness, Andrew P Jackson, Clive G Jackson, Lee P Kingston, Matthew W D Perry, Andrew R J Ross, Paul A Rugman, Sasvinder S Sidhu, Michael Sullivan, David A Taylor-Fishwick, P Craig Walker, Yvonne M Whitehead, David J Wilkinson, Andrew Wright and David K Donald

Published online: 30 October 2005 | doi 10.1038/nchembio744

First paragraph | Full text | PDF

C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L

Sylvie Fournel, Sébastien Wieckowski, Weimin Sun, Nathalie Trouche, Hélène Dumortier, Alberto Bianco, Olivier Chaloin, Mohammed Habib, Jean-Christophe Peter, Pascal Schneider, Bernard Vray, René E Toes, Rienk Offringa, Cornelis J M Melief, Johan Hoebeke and Gilles Guichard

Published online: 06 November 2005 | doi 10.1038/nchembio746

First paragraph | Full text | PDF |

Analysis of drug-induced effect patterns to link structure and side effects of medicines

Anton F Fliri, William T Loging, Peter F Thadeio and Robert A Volkmann

Published online: 06 November 2005 | doi 10.1038/nchembio747

Abstract | Full text | PDF |

Actin is the primary cellular receptor of bistramide A

Alexander V Statsuk, Ruoli Bai, Jeremy L Baryza, Vishal A Verma, Ernest Hamel, Paul A Wender and Sergey A Kozmin

Published online: 13 November 2005 | doi 10.1038/nchembio748

First paragraph | Full text | PDF |

Small molecules that delay S phase suppress a zebrafish bmyb mutant

Howard M Stern, Ryan D Murphey, Jennifer L Shepard, James F Amatruda, Christian T Straub, Kathleen L Pfaff, Gerhard Weber, John A Tallarico, Randall W King and Leonard I Zon

Published online: 13 November 2005 | doi 10.1038/nchembio749

First paragraph | Full text | PDF |