[GRG] synthetic amino acid enhances drug potency


Contact: Nik Papageorgiou
Ecole Polytechnique Fédérale de Lausanne

A new synthetic amino acid for an emerging class of drugs

One of the greatest challenges in modern medicine is developing
drugs that are highly effective against a target, but with minimal
toxicity and side-effects to the patient. Such properties are
directly related to the 3D structure of the drug molecule. Ideally,
the drug should have a shape that is perfectly complementary to a
disease-causing target, so that it binds it with high specificity.
Publishing in Nature Chemistry, EPFL scientists have developed a
synthetic amino acid that can impact the 3D structure of bioactive
peptides and enhance their potency.

Peptides and proteins as drugs

Many of the drugs we use today are essentially naturally-occurring
peptides (small) and proteins (large), both of which are made up
with the amino acids found in all living organisms. Despite the
enormous variety of peptides and proteins, there are only twenty
natural amino acids, each with a different structure and chemical
properties. When strung together in a sequence, amino acids create
peptides and proteins with different 3D structures and,
consequently, different biological functions.

Until recently, the vast majority of amino acid-based drugs were
the kinds occurring in nature: hormones such as insulin,
antibiotics such as vancomycin, immunosuppressive drugs such as
cyclosporine etc. But the mounting burden of diseases means that
newer and more effective medications must be developed; for
example, bacterial resistance is growing globally, pushing our need
for novel antibiotics. One way to address this need is the cutting-
edge field of directed evolution, which mimics natural selection in
the lab to evolve and develop new peptides and proteins.

A new amino acid for new peptides

The team of Christian Heinis at EPFL has developed a synthetic
amino acid whose unique structure can considerably increase the
effectiveness of therapeutic peptides and proteins. The synthetic
amino acid has a very similar structure to a natural amino acid
called cysteine. Cysteine is unique among the twenty natural amino
acids because it contains a sulfur group. This allows it to form a
bridge with another cysteine, and thereby influence the overall 3D
structure – and function – of a peptide or protein.

The EPFL researchers initially designed five cysteine-like amino
acids, all with one crucial change: each one could form two bridges
instead of just one. The team achieved this by replacing cysteine’s
single sulfur group with a branch containing two sulfur groups.
After synthesizing the five new amino acids, the team integrated
them into the structure of two bioactive peptides, one that
inhibits an enzyme implicated in cancer, and one blocking a
receptor found in neurons.

Testing only a handful of cyclic peptides with the synthetic amino
acid, Heinis’ team was able to identify several peptides that
showed enhanced activities. The best inhibitor of the neuron
receptor was 8-fold improved and the best protease inhibitor had
even a 40-fold higher activity.

“This was unexpected”, says Christian Heinis. “Usually when you
tamper with a natural molecule, you end up making it worse. In this
case, we found the exact opposite, which is very exciting.”

The emerging class of bicyclic peptides

The team focuses on therapeutics, where they have a strong
background in developing “bicyclic” peptides – peptides that
contain two rings in their structure. Bicyclic peptides have grown
into a new class of therapeutic peptides that can be used on
disease target that conventional small molecules or large
antibodies cannot reach. Heinis’ group has generated bicyclic
peptides against a range of disease targets using directed
evolution. “In our work with bicyclic peptides, we learned that
wide structural diversity in peptide libraries is key for achieving
good binding. With this new amino acid, it is possible to produce
highly diverse peptide structures.”

Heinis aims now to use the new amino acid in directed evolution
experiments. Its structural features and its ability to efficiently
make cyclic peptides makes the synthetic amino acid a promising
candidate for developing new, effective polycyclic peptides for
targeted therapy.



Chen S. Gopalakrishnan R, Schaer T, Marger F, Hovius R, Bertrand D,
Pojer F, Heinis C. Di-thiol amino acids can structurally shape and
enhance the ligand-binding properties of polypeptides. Nature
Chemistry 31 August 2014. DOI: 10.1038/nchem.2043

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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