Intrinsically disordered proteins as potential drug targets

Question

Intrinsically disordered proteins (IDPs) are a class of proteins that do not adopt a stable secondary or tertiary structure under physiological conditions in vitro, but still have biological functions. Many IDPs are implicated in cancer, neurodegenerative diseases, and diabetes, which makes them attractive drug targets. Are there any successful examples of that? Are there any drugs which disrupt protein-protein interactions (where one of the proteins is an IDP)?

Answer 1

IDPs are indeed attractive drug targets and there are ongoing efforts to develop drug molecules that block interactions between a disordered and a structured protein. According to this relatively recent paper, however, these efforts have not brought a drug on the market, yet.

A few promising studies have shown drug-like molecules that inhibit protein-protein interactions based on intrinsic disorder of one of the partners and target:

• oncogenic fusion protein EWS-FLI1 and RNA helicase A. A small molecule has been found that targets the disordered region of EWS-FLI1, blocks the interaction with the helicase and inhibits growth of Ewing's sarcoma.

• p53 tumor supressor and its interactor Mdm2. Mdm2, by binding to an intrinsically disordered region of p53, targets p53 for ubiquitination and also causes it to be transported out of the nucleus. Promising small molecules have been found that associate with Mdm2 and thereby block its interaction with p53.

• c-Myc oncoprotein and the interaction with its partner Max protein. This study demonstrates two small molecules that bind to c-Myc and stabilize its disordered conformation, which inhibits its interaction with the Max protein.

The challenge in targeting protein-protein interactions for therapies stems largely from the fact, that the protein-protein contact surfaces are much larger than those involved in protein–small-molecule interactions (1,500–3,000 Ų and (300–1,000 Ų, respectively) [2]. They are often flat and have no defined binding pocket. Also, IDPs often don't bind natural small ligands, that could act as starting points in developing drugs.

You may find this paper helpful:

Metallo SJ, Intrinsically disordered proteins are potential drug targets, Curr Opin Chem Biol. 2010 14(4): 481–488.

BTW: for a comprehensive, manually curated list of disordered proteins and regions, please check the Database of Protein Disorder.

Answer 2

I have been working on this problem for quite some time now and believe me getting specific binding is a real issue with IDRs. Also, since these regions don't contribute to the core structure of the protein, the residues are less conserved (more prone to mutations). So in the case of evolving drug-resistance contributing proteins this becomes a bottleneck.

I have done some work on IDPs as potential drug targets: Unraveling the potential of intrinsically disordered proteins as drug targets: application to Mycobacterium tuberculosis.

But the concept has been taken well by even the conventional structural biologists.

As the paper suggests, my work is focused on Mycobacterium tuberculosis. Multi-Drug Resistant (MDR) and Extensively Drug Resistant (XDR) forms of TB have added to the tuberculosis loads not only in the developing but also developed nations. Drug resistance has been associated with proteins (mostly those involved in transport and metabolism) that have helped this pathogen grow resistant to the first line drugs or more. I refer to such proteins as "Drug resistance associated proteins".