Semaphorins and plexins as therapeutic targets

Key Points

  • Semaphorins are membrane-bound or diffusible factors that regulate key cellular functions and are involved in cell–cell communication. Most of the effects of semaphorins are mediated by plexins.

  • Work over the past decade has revealed crucial functions of the semaphorin–plexin system in mammalian physiology. It has also become clear that semaphorins and plexins have important roles in many pathophysiological processes and that they represent novel targets for drugs to prevent or treat various diseases.

  • Several semaphorins and plexins are critically involved in tumour growth and metastasis by controlling tumour development and progression via the formation of autocrine signalling loops in cancer cells, as well as by regulating the interaction of different cells within the tumour.

  • Semaphorins and plexins have also been found to control immune functions by regulating immune cell activation, differentiation and trafficking, and several semaphorins and plexins have crucial roles in inflammatory and autoimmune diseases.

  • Semaphorin 3A and semaphorin 4D have important roles in promoting bone formation and resorption, respectively, and semaphorin 3A and inhibitors of semaphorin-4D-induced signalling have been suggested as potential agents to prevent bone loss.

  • Semaphorin 3A and semaphorin 3E appear to promote particular diseases of the microvasculature, and therapies that target these semaphorins and their downstream signalling events may be promising approaches to treat microvascular diseases.

  • Notably, semaphorin 3A has been suggested to be a critical factor that impedes the regeneration of the central nervous system, and several experimental drugs have been developed to inhibit semaphorin 3A activity in order to promote central nervous system regeneration.

  • Several semaphorins and plexins have been identified as potential targets for drugs to treat particular diseases, such as cancer, immunological disorders, osteoporosis or microvascular diseases. The development of specific ligands or inhibitors is ongoing; indeed, antibodies that are directed against semaphorin 4D are currently being tested in clinical trials.

Abstract

Semaphorins are membrane-bound or diffusible factors that regulate key cellular functions and are involved in cell–cell communication. Most of the effects of semaphorins are mediated by plexins. Work over the past decade has revealed crucial functions of the semaphorin–plexin system in mammalian physiology. It has also become clear that semaphorins and plexins have important roles in many pathophysiological processes, including cancer, immunological diseases and bone disorders, and that they represent novel targets for drugs to prevent or treat various diseases. This Review summarizes the functions of the mammalian semaphorin–plexin system as well as its role in diseases and discusses emerging strategies to pharmacologically target semaphorin–plexin signalling.

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Figure 1: Semaphorins and their receptors: plexins and neuropilins.
Figure 2: Semaphorin–plexin signalling and binding interfaces.
Figure 3: Some functions of semaphorins and plexins in tumour growth and progression.
Figure 4: Some functions of semaphorins and their receptors in different phases of the immune response.
Figure 5: Some roles of semaphorins and their receptors in bone remodelling.
Figure 6: Structures of xanthofulvin, vinaxanthone and SICHI.

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Correspondence to Thomas Worzfeld or Stefan Offermanns.

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T.W. and S.O. hold a patent on B-type plexin antagonists and uses thereof.

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Angiogenesis

Process by which new blood vessels form from pre-existing vessels.

β-propeller

Type of protein architecture characterized by several blade-shaped sheets that each typically consist of four antiparallel β-strands.

GTPase-activating protein

(GAPs). Protein that binds to activated GTP-bound guanine nucleotide-binding proteins and stimulates their GTPase activity, thereby, in most cases, terminating signalling activity.

PDZ domain

Protein domain of 80–90 amino acids that binds to a short region of the carboxyl terminus of other proteins.

Guanine nucleotide exchange factors

(GEFs). Group of proteins that bind to guanine nucleotide-binding proteins and stimulate the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP), usually leading to activation of signalling.

Epithelial–mesenchymal transition

(EMT). Process by which epithelial cells acquire migratory and invasive properties and increase their metastatic potential.

Experimental autoimmune encephalomyelitis

(EAE). Animal model resembling the human disease multiple sclerosis.

Microglia

Resident macrophages of the central nervous system.

Atopic dermatitis

Relapsing skin disorder, often caused by allergic reactions.

Osteoporosis

Bone disorder characterized by decreased bone mass and density.

Vitreous humour

Gel that fills the space between the retina and the lens of the eyeball.

Oligodendrocyte

Type of glial cell which forms a myelin sheath and thereby provides support and insulation to the long projections (axons) of nerve cells.

Pyramidotomy

Surgical procedure by which the corticospinal tract — which conducts impulses from the brain to the spinal cord and thereby allows the execution of precise voluntary movements — is severed.

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Worzfeld, T., Offermanns, S. Semaphorins and plexins as therapeutic targets. Nat Rev Drug Discov 13, 603–621 (2014). https://doi.org/10.1038/nrd4337

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