Present and future drugs to interfere with cytoskeletal functions

Disregarding feasibility of use, what types of drugs are in principle available to interfere with cytoskeleton functions?

1. Compounds that interfere with microtubule or F-actin stability and dynamics: These drugs are important because we know that microtubules and microtubule dynamics and F-actin are essential in axon regeneration and in synaptic function (rearrangement of F-actin and invasion of microtubules into spines in response to synaptic activity). One advantage of these drugs is that they are specific for the cytoskeleton (as opposed to drugs that target posttranslational modification enzymes; see below).
2. Compounds directed against protein kinases that regulate cytoskeleton-associated proteins: of these, ROCK inhibitors are already being tested for their effect in promoting regeneration. Inhibitors for other kinases (GSK-3, cdk5, JNK1, 2 and 3, etc) are available, but kinase inhibitors in principle have two problems: 1) most of them are not specific for a single kinase and 2) even if they were, they would affect not only the cytoskeleton but also non-cytoskeletal targets of these kinases. However, in keeping with the idea that systemic targeting of the ubiquitous cytoskeleton can be beneficial (example schizophrenia), we might also consider that systemic targeting of a pleiotropic kinase could be an option. An even broader spectrum of effects would be expected from phosphatase inhibitors.
3. Compounds that target enzymes involved in posttranslational modifications of cytoskeletal components: Good examples are drugs inhibiting acetylation (HDAC inhibitors) or nitrosylation (nNOS). These too will not only affect cytoskeletal proteins, but also other cellular components, which could be considered an advantage or a disadvantage.
4. Compounds that interfere with second messengers: for example, drugs targeting cAMP, cGMP (phosphodiesterase inhibitors) and calcium (channel blockers) have pleiotropic effects including indirect effects on the cytoskeleton.

To my knowledge we have currently not available: drugs that interfere directly with specific MAPs, actin-associated proteins or motor proteins. To develop strategies to targets these proteins specifically could be one major goal of an extended commitment to neural cytoskeleton research.

Friedrich Propst