Abundant `secret doors' on human proteins could reshape drug discovery
Identification of hidden vulnerabilities on surface of `undruggable'
proteins could transform treatment of disease
Date:
April 6, 2022
Source:
Center for Genomic Regulation
Summary:
A groundbreaking new technique reveals the existence of a multitude
of previously hidden therapeutic targets that control protein
function and which could, in theory, be targeted to dramatically
change the course of diseases as varied as dementia, cancer and
infectious diseases. The approach, which finds that the 'secret
doors' are abundant and identifiable, could be a game changer
for drug discovery, leading to safer, smarter and more effective
medicines. It enables research labs around the world to find
and exploit vulnerabilities in any protein - - including those
previously thought 'undruggable'.
FULL STORY ==========================================================================
The number of potential therapeutic targets on the surfaces of human
proteins is much greater than previously thought, according to the
findings of a new study in the journal Nature.
==========================================================================
A ground-breaking new technique developed by researchers at the Centre
for Genomic Regulation (CRG) in Barcelona has revealed the existence of
a multitude of previously secret doors that control protein function and
which could, in theory, be targeted to dramatically change the course
of conditions as varied as dementia, cancer and infectious diseases.
The method, in which tens of thousands of experiments are performed at
the same time, has been used to chart the first ever map of these elusive targets, also known as allosteric sites, in two of the most common human proteins, revealing they are abundant and identifiable.
The approach could be a game changer for drug discovery, leading to
safer, smarter and more effective medicines. It enables research labs
around the world to find and exploit vulnerabilities in any protein -- including those previously thought 'undruggable'.
"Not only are these potential therapeutic sites abundant, there is
evidence they can be manipulated in many different ways. Rather than
simply switching them on or off, we could modulate their activity like a thermostat. From an engineering perspective, that's striking gold because
it gives us plenty of space to design 'smart drugs' that target the bad
and spare the good," explains Andre' Faure, postdoctoral researcher at
the CRG and co-first author of the paper.
Proteins play a central role in all living organisms and carry out vital functions such as providing structure, speeding up reactions, acting as messengers or fighting disease. They are made of amino acids, folding
into countless different shapes in three-dimensional space. The shape
of a protein is crucial for its function, with just one mistake in an
amino acid sequence resulting in potentially devastating consequences
for human health.
========================================================================== Allostery is one of the great unsolved mysteries of protein function.
Allosteric effects occur when a molecule binds to the surface of a
protein, which in turn causes changes at a distant site in the same
protein, regulating its function by remote control. Many disease-causing mutations, including numerous cancer drivers, are pathological because
of their allosteric effects.
Despite their fundamental importance, allosteric sites are incredibly
difficult to find. This is because the rules governing how proteins work
at the atomic level are hidden out of sight. For example, a protein
might shapeshift in the presence of an incoming molecule, revealing
hidden pockets deep within its surface that are potentially allosteric
but not identifiable using conventional structure determination alone.
Drug hunters have traditionally designed treatments that target a
protein's active site, the small region where chemical reactions occur or targets are bound. The downside of these drugs, also known as orthosteric drugs, is that active sites of many proteins look very similar and so
drugs tend to bind and inhibit many different proteins at once, leading
to potential side effects. In comparison, the specificity of allosteric
sites means that allosteric drugs are some of the most effective types
of medication currently available. Many allosteric drugs, which treat
various conditions ranging from cancer to AIDS to hormone disorders,
have been discovered by accident.
The authors of the study addressed this challenge by developing a
technique called double deep PCA (ddPCA), which they describe as a 'brute
force experiment'. "We purposefully break things in thousands of different
ways to build a complete picture of how something works," explains
ICREA Research Professor Ben Lehner, Coordinator of the Systems Biology programme at the CRG and author of the study. "It's like suspecting
a faulty spark plug, but instead of only checking that, the mechanic
dismantles the entire car and checks it piece by piece. By testing ten
thousand things in one go we identify all the pieces that really matter."
The method works by changing the amino acids that make up a protein,
resulting in thousands of different versions of the protein with just
one or two differences in the sequence. The effects of the mutations
are then tested all at the same time in living cells in the laboratory.
"Each cell is a tiny factory making a different version of the protein. In
a single test tube we have millions of different factories and so we can
very rapidly test how well all the different versions of a protein work,"
adds Dr.
Lehner. The data collected from the experiments is fed into neural
networks, algorithms that analyze data by mimicking the way the human
brain operates, which result in comprehensive maps that pinpoint the
location of allosteric sites on the surfaces of proteins.
One of the great advantages of the method is that it is an affordable
technique accessible to any research lab around the world. "It massively simplifies the process needed to find allosteric sites, with the
technique working at a level of accuracy better than several different
more expensive and time-consuming lab methods," says Ju'lia Domingo,
co-first author of the study. "Our hope is that other scientists use the technique to rapidly and comprehensively map the allosteric sites of human proteins one by one." One of the longer-term benefits of the technique
is its potential to study the function and evolution of proteins. The
authors of the study believe that, if scaled up, the method could one day result in advances that can precisely predict the properties of proteins
from their amino acid sequences. If successful, the authors argue this
would usher in a new era of predictive molecular biology, allowing much
faster development of new medicine and clean, biology-based industry.
"While some tools can predict a protein's structure by reading its
sequence, our method goes one step further by telling us how a protein
works. This is part of a bigger vision to make biology as engineerable
as aeroplanes, bridges or computers. We have faced the same challenges
for over 70 years, but it turns out they are more tractable than
we previously thought. If we succeed it will open a new field with unprecedented possibilities," concludes Dr. Lehner.
========================================================================== Story Source: Materials provided by Center_for_Genomic_Regulation. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. Andre J. Faure, Ju'lia Domingo, Jo"rn M. Schmiedel, Cristina
Hidalgo-
Carcedo, Guillaume Diss, Ben Lehner. Mapping the energetic and
allosteric landscapes of protein binding domains. Nature, 2022;
604 (7904): 175 DOI: 10.1038/s41586-022-04586-4 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220406132418.htm
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