Precision medicine

Hitting chaos: the revolutionary strategy against disordered proteins

Faced with resistant tumours and neurodegenerative diseases, researchers explore a new protein universe: that of disorder

by Francesca Cerati

20 June 2025

3' min read

Key points

The Italian study that challenges the paradigm
Why messy proteins are so hard to hit
Open challenges and perspectives

3' min read

For decades, molecular biology has lived in the shadow of a dogma: to function, a protein must have a stable three-dimensional structure. However, one class of proteins escapes this rule, despite playing central roles in cellular processes: these are the intrinsically disordered proteins (IdPs). Without a fixed shape, these proteins take on different configurations depending on the environment, binding or chemical changes. Their dynamic behaviour makes them key players in cell regulation and, when something goes wrong, potential actors in the most complex diseases: cancer, Alzheimer's, Parkinson's, chronic inflammation.

A recent review in Nature Reviews Drug Discovery defines IdPs as the next big hurdle - but also an opportunity in drug discovery. These proteins, which are highly flexible and often lack stable binding sites, have long been considered 'untreatable' with classical pharmacological approaches. However, thanks to the integration of advanced experimental techniques (such as Nmr, Saxs, single-molecule Fret) and advanced computational methods, a new strategy is emerging: 'i-mods', small compounds designed to bind to IdPs, stabilising or inhibiting their specific functions.

The Italian study that challenges the paradigm

This emerging scenario includes the study led by Barbara Zambelli, associate professor at the Department of Pharmacy and Biotechnology at the University of Bologna, who has identified the Ndrg1 protein as a promising target against lung cancer. The innovative aspect? The team focused not on the 'rigid' part of the protein, but on a disordered terminal region, responsive to environmental stimuli such as the presence of nickel - a known carcinogen found in smoke and smog.

Ndrg1 is overexpressed in the presence of pollutants and associated with tumour aggressiveness and treatment resistance. Its disordered sequence, in particular, changes shape upon interactions with lipids and metals. A key modification is phosphorylation, which alters the protein's ability to anchor itself to cell membranes. Inhibiting this function could turn off a tumour switch before it even goes off.

But the real revolution is conceptual: 'The study abandons the classic 'key-lock' model for the drug-target interaction, proposing to target the mobility of the protein itself,' explains Zambelli, who presented the study at the University of Trieste at the conference of the Chemical Division of Biological Systems of the Italian Chemical Society. 'The goal is to identify molecules that, by binding to the disordered region of Ndrg1, reduce its flexibility, blocking its pathological function.

Why disordered proteins are so hard to hit

IdPs account for about a third of mammalian proteins and are often crucial in regulatory processes such as gene transcription, biomolecular condensate formation and intracellular signalling. Their dynamic nature allows them to act as 'molecular hubs' but prevents the identification of stable binding sites, making it very complex to design effective drugs.

However, recent examples show that it is possible. Some experimental drugs are already targeting dysregulated proteins involved in tumours (such as Myc and p53), neurodegenerative diseases (such as α-synuclein and tau) and autoimmune diseases. Zambelli's study is among the first to attempt this approach in the context of lung cancer, opening up a new avenue to selectively target diseased cells.

Open Challenges and Prospects

There is still a long way to go. Most i-mods currently under study have binding affinities in the micromolar range, too low for the clinic. But advances in molecular simulations and high-throughput screening techniques could bridge the gap. Moreover, the possibility of modulating the formation of pathological aggregates (such as those observed in Alzheimer's or amyotrophic lateral sclerosis) opens up new frontiers in molecular medicine.

In short, disordered proteins are no longer a biological enigma, but a therapeutic promise. This is demonstrated by the Italian study on Ndgr1, which breaks the mould and suggests that sometimes the absence of form may be the key to stopping a disease.