Study identifies path to safer drugs for heart disease, cancer

March 23, 2014, Massachusetts General Hospital
Left: the two peptide chains of an integrin receptor, colored red and blue, extend through the cell membrane into the extracellular space. Center: when bound to the common form of the FN10 ligand or to a ligand-mimicking molecule, the integrin becomes activated, changing its shape and causing the cell to become sticky. Right: binding of the high-affinity form of FN10 does not cause the integrin to shape-shift, blocking its activation. Credit: M. Amin Arnaout, MD, Massachusetts General Hospital

Massachusetts General Hospital (MGH) investigators may have found a way to solve a problem that has plagued a group of drugs called ligand-mimicking integrin inhibitors, which have the potential to treat conditions ranging from heart attacks to cancer metastasis. In a Nature Structural & Molecular Biology paper receiving advance online publication, the researchers provide a structural basis for the design of new and safer integrin inhibitors.

Integrins are receptor proteins found on the surface of cells that determine whether or not cells adhere to adjacent cells and the surrounding extracellular matrix. Under normal circumstances, integrins only become activated – which allows them to bind to other cells or extracellular molecules – in response to specific signals from within the cell. If integrins become overactive, cells become too "sticky" – leading to clogged arteries, pathological inflammation, the excess tissue growth called fibrosis or the spread of cancer. Current drugs developed to inhibit integrin activation by mimicking the shape of ligands – the molecules that interact with receptors – have had unintended effects in some patients, and as a result only a handful have received FDA approval.

"Integrins have an intrinsic ability to shape-shift when they switch from an inactive to an active, adhesive state," explains M. Amin Arnaout, MD, director of the MGH Leukocyte Biology Program and the Inflammation and Structural Biology Program, senior author of the study. "Unfortunately, under some circumstances the integrin inhibitors that have been developed to date can inadventently induce this shape shifting, and use of these drugs have produced serious, sometimes fatal side effects such as excessive bleeding."

In their search for drugs that would not induce these complications, the MGH team focused on an extracellular matrix protein called fibronectin, which binds to an integrin called αvβ3. Their detailed structural analysis of the bond between αvβ3 and various forms of FN10, the fibronectin molecule that interacts with αvβ3, identified a high-affinity version of FN10 that binds more strongly than the common form without causing unintended receptor activation. This first report of the three-dimensional atomic structure of an integrin binding with a ligand-mimicking molecule that does not cause inadvertent activation could enable the design of a new generation of integrin inhibitors without the complications that have limited their application.

Explore further: Integrin cell adhesion receptors are risky cancer drug targets

More information: Structural basis for pure antagonism of integrin αVβ3 by a high-affinity form of fibronectin, DOI: 10.1038/nsmb.2797

Related Stories

Integrin cell adhesion receptors are risky cancer drug targets

February 11, 2014
A possible cancer treatment strategy might in fact lead to increased metastasis in some cases. This finding from a team of LACDR researchers led by Erik Danen made the cover of the February 11 edition of Science Signaling.

Scientists make advance in cancer research

January 3, 2014
A protein that has been at the centre of cancer drug design for the last 20 years should not be given up on according to new research from the University of East Anglia (UEA). The most advanced version of αvβ3-integrin ...

DGK-alpha helps cancer cells gain traction and mobilize

January 23, 2012
Metastasizing cancer cells often express integrins that provide better traction. A new study in The Journal of Cell Biology reveals how a lipid-converting enzyme helps the cells mobilize these integrins.

Recommended for you

More surprises about blood development—and a possible lead for making lymphocytes

January 22, 2018
Hematopoietic stem cells (HSCs) have long been regarded as the granddaddy of all blood cells. After we are born, these multipotent cells give rise to all our cell lineages: lymphoid, myeloid and erythroid cells. Hematologists ...

How metal scaffolds enhance the bone healing process

January 22, 2018
A new study shows how mechanically optimized constructs known as titanium-mesh scaffolds can optimize bone regeneration. The induction of bone regeneration is of importance when treating large bone defects. As demonstrated ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.