In this 21st Century Chemist profile, New York University chemist Kent Kirshenbaum explains his work folding long-chain molecules into synthetic molecules called peptoids, that might be developed into, among other things, "hunter-killer" antibiotics that target and destroy lethal drug-resistant bacteria.
Origami Chemistry: NYU Chemist Folds Molecules
TOM COSTELLO, reporting:
Kent Kirshenbaum is an architect, of sorts. He designs and builds incredible new structures in his lab at New York University. Only his "cathedrals" are so tiny and so complex, he needs special x-ray microscopes to see them.
It’s that source of creativity, that source of imagination that’s really crucial, similar to perhaps an architect sitting down for the first time and trying to figure out what’s going to be the exact three-dimensional arrangement of a new building that is going to be constructed.
COSTELLO: Kirshenbaum is a bioorganic chemist who is funded by the National Science Foundation. He and his team are engineering new molecules that are modeled after ones found in nature. These new synthetic, man-made, molecules are called peptoids.
KIRSHENBAUM: We call them peptoids because they’re very similar to the peptides that are used to form proteins.
COSTELLO: Peptides are small proteins, generally less than 100 amino acids long, linked together by a peptide bond. Peptoids are modified peptides, in which, the side chain groups are connected to the main chain nitrogen atom instead of the carbon atom. This unnatural branching pattern allows peptoids to fold into stronger, various shapes like helices, loops, and sheets. Kirshenbaum first became fascinated with these types of structures as a Ph.D student, when one professor inspired him to pursue a career in chemistry.
KIRSHENBAUM: He said “why is it that only nature has figured out this folding code? Why can’t we go into the lab and create chain molecules that can also fold in very particular ways?” That comment grabbed me, it electrified me, and it’s really motivated everything that I have done in the laboratory since then.
COSTELLO: Today, Kirshenbaum is designing and building new structures that have never been created or imagined before. Some of the molecules he and his team are designing could be used to fight diseases like cancer, Alzheimer's and deadly bacteria like MRSA, a highly resistant strain of Staphylococcus Aureus, commonly known as "staph."
KIRSHENBAUM: There is a terrible problem right now in hospital clinics that bacteria are becoming evolved to avoid the action of the antibiotics that are typically used.
COSTELLO: MRSA is an infectious bacteria that's resistant to nearly all known antibiotics. Kirshenbaum and his team are trying to design a new antibiotic that could fight MRSA and other bacteria by hunting down, binding to, and destroying dangerous bacterial cells in the body.
KIRSHENBAUM: You can think of them as being hunter-killer type molecules whose shape will allow them to bind specifically to that protein target that we’ve identified within the cell as being a prime candidate for new drug therapy.
COSTELLO: But in order to get these new molecules to fold into just the right shape, Kirshenbaum needs to assemble chains of amino acids into a specific pattern. The placement of each molecule in this pattern determines how the chain will fold and what shape it will eventually have.
KIRSHENBAUM: If we’re very careful about this assembly then we’ll be able to position a positive charge where we want it, a negative charge where we want it. Those will seek to come closer together and that will provide the kind of force that will fix, constrain, orient the chain molecule into a very particular arrangement.
COSTELLO: To find out if the arrangement of the molecule matches the one he set out to design, Kirshenbaum and his team use a special machine called an x-ray diffractometer, which reveals the diffraction pattern of the sample. The diffraction pattern is the pattern that's formed as light waves scatter around atoms. This pattern, which is different for each unique arrangement of atoms in a structure, gives Kirshenbaum's team the information they need to find out the exact structure of the molecule.
KIRSHENBAUM: If we’ve done our job properly, the x-ray defraction experiments will tell us that we’ve generated the right fold, the right arrangement of the individual chemical groups and establish the proper type of molecular architecture that we’re looking for.
COSTELLO: While no drug therapies are yet on the market, Kirshenbaum says he's excited by the endless possibilities of building organic structures that may one day help improve public health.
KIRSHENBAUM: The possibilities for folding a chain-like molecule are astronomical. When we go and we find that we’ve designed one particular type of arrangement, it really just completely astounds me. And the fact that we are able to identify one particular arrangement of the atoms in those molecules is really exciting.
The modern medical era began when an absent-minded British scientist named Alexander Fleming returned from vacation to find that one of the petri dishes he forgot to put away was covered in a bacteria-killing mold. He had discovered penicillin, the world's first antibiotic.
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