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Friday, March 27th, 2020

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    9:46a
    An experimental peptide could block Covid-19

    The research described in this article has been published on a preprint server but has not yet been peer-reviewed by scientific or medical experts.

    In hopes of developing a possible treatment for Covid-19, a team of MIT chemists has designed a drug candidate that they believe may block coronaviruses’ ability to enter human cells. The potential drug is a short protein fragment, or peptide, that mimics a protein found on the surface of human cells.

    The researchers have shown that their new peptide can bind to the viral protein that coronaviruses use to enter human cells, potentially disarming it.

    “We have a lead compound that we really want to explore, because it does, in fact, interact with a viral protein in the way that we predicted it to interact, so it has a chance of inhibiting viral entry into a host cell,” says Brad Pentelute, an MIT associate professor of chemistry, who is leading the research team.

    The MIT team reported its initial findings in a preprint posted on bioRxiv, an online preprint server, on March 20. They have sent samples of the peptide to collaborators who plan to carry out tests in human cells.

    Molecular targeting

    Pentelute’s lab began working on this project in early March, after the Cryo-EM structure of the coronavirus spike protein, along with the human cell receptor that it binds to, was published by a research group in China. Coronaviruses, including SARS-CoV-2, which is causing the current Covid-19 outbreak, have many protein spikes protruding from their viral envelope.

    Studies of SARS-CoV-2 have also shown that a specific region of the spike protein, known as the receptor binding domain, binds to a receptor called angiotensin-converting enzyme 2 (ACE2). This receptor is found on the surface of many human cells, including those in the lungs. The ACE2 receptor is also the entry point used by the coronavirus that caused the 2002-03 SARS outbreak.

    In hopes of developing drugs that could block viral entry, Genwei Zhang, a postdoc in Pentelute’s lab, performed computational simulations of the interactions between the ACE2 receptor and the receptor binding domain of the coronavirus spike protein. These simulations revealed the location where the receptor binding domain attaches to the ACE2 receptor — a stretch of the ACE2 protein that forms a structure called an alpha helix.

    “This kind of simulation can give us views of how atoms and biomolecules interact with each other, and which parts are essential for this interaction,” Zhang says. “Molecular dynamics helps us narrow down particular regions that we want to focus on to develop therapeutics.”

    The MIT team then used peptide synthesis technology that Pentelute’s lab has previously developed, to rapidly generate a 23-amino acid peptide with the same sequence as the alpha helix of the ACE2 receptor. Their benchtop flow-based peptide synthesis machine can form linkages between amino acids, the buildings blocks of proteins, in about 37 seconds, and it takes less than an hour to generate complete peptide molecules containing up to 50 amino acids.

    “We’ve built these platforms for really rapid turnaround, so I think that’s why we’re at this point right now,” Pentelute says. “It’s because we have these tools we’ve built up at MIT over the years.”

    They also synthesized a shorter sequence of only 12 amino acids found in the alpha helix, and then tested both of the peptides using equipment at MIT’s Biophysical Instrumentation Facility that can measure how strongly two molecules bind together. They found that the longer peptide showed strong binding to the receptor binding domain of the Covid-19 spike protein, while the shorter one showed negligible binding.

    Many variants

    Although MIT has been scaling back on-campus research since mid-March, Pentelute’s lab was granted special permission allowing a small group of researchers to continue to work on this project. They are now developing about 100 different variants of the peptide in hopes of increasing its binding strength and making it more stable in the body.

    “We have confidence that we know exactly where this molecule is interacting, and we can use that information to further guide refinement, so that we can hopefully get a higher affinity and more potency to block viral entry in cells,” Pentelute says.

    In the meantime, the researchers have already sent their original 23-amino acid peptide to a research lab at the Icahn School of Medicine at Mount Sinai for testing in human cells and potentially in animal models of Covid-19 infection.

    While dozens of research groups around the world are using a variety of approaches to seek new treatments for Covid-19, Pentelute believes his lab is one of a few currently working on peptide drugs for this purpose. One advantage of such drugs is that they are relatively easy to manufacture in large quantities. They also have a larger surface area than small-molecule drugs.

    “Peptides are larger molecules, so they can really grip onto the coronavirus and inhibit entry into cells, whereas if you used a small molecule, it’s difficult to block that entire area that the virus is using,” Pentelute says. “Antibodies also have a large surface area, so those might also prove useful. Those just take longer to manufacture and discover.”

    One drawback of peptide drugs is that they typically can’t be taken orally, so they would have to be either administered intravenously or injected under the skin. They would also need to be modified so that they can stay in the bloodstream long enough to be effective, which Pentelute’s lab is also working on.

    “It’s hard to project how long it will take to have something we can test in patients, but my aim is to have something within a matter of weeks. If it turns out to be more challenging, it may take months,” he says.

    In addition to Pentelute and Zhang, other researchers listed as authors on the preprint are postdoc Sebastian Pomplun, grad student Alexander Loftis, and research scientist Andrei Loas.

    2:00p
    Energy-harvesting design aims to turn Wi-Fi signals into usable power

    Any device that sends out a Wi-Fi signal also emits terahertz waves —electromagnetic waves with a frequency somewhere between microwaves and infrared light. These high-frequency radiation waves, known as “T-rays,” are also produced by almost anything that registers a temperature, including our own bodies and the inanimate objects around us.

    Terahertz waves are pervasive in our daily lives, and if harnessed, their concentrated power could potentially serve as an alternate energy source. Imagine, for instance, a cellphone add-on that passively soaks up ambient T-rays and uses their energy to charge your phone. However, to date, terahertz waves are wasted energy, as there has been no practical way to capture and convert them into any usable form.

    Now physicists at MIT have come up with a blueprint for a device they believe would be able to convert ambient terahertz waves into a direct current, a form of electricity that powers many household electronics.

    Their design takes advantage of the quantum mechanical, or atomic behavior of the carbon material graphene. They found that by combining graphene with another material, in this case, boron nitride, the electrons in graphene should skew their motion toward a common direction. Any incoming terahertz waves should “shuttle” graphene’s electrons, like so many tiny air traffic controllers, to flow through the material in a single direction, as a direct current.

    The researchers have published their results today in the journal Science Advances, and are working with experimentalists to turn their design into a physical device.

    “We are surrounded by electromagnetic waves in the terahertz range,” says lead author Hiroki Isobe, a postdoc in MIT’s Materials Research Laboratory. “If we can convert that energy into an energy source we can use for daily life, that would help to address the energy challenges we are facing right now.”

    Isobe’s co-authors are Liang Fu, the Lawrence C. and Sarah W. Biedenharn Career Development Associate Professor of Physics at MIT; and Su-yang Xu, a former MIT postdoc who is now an assistant professor chemistry at Harvard University.

    Breaking graphene’s symmetry

    Over the last decade, scientists have looked for ways to harvest and convert ambient energy into usable electrical energy. They have done so mainly through rectifiers, devices that are designed to convert electromagnetic waves from their oscillating (alternating) current to direct current.

    Most rectifiers are designed to convert low-frequency waves such as radio waves, using an electrical circuit with diodes to generate an electric field that can steer radio waves through the device as a DC current. These rectifiers only work up to a certain frequency, and have not been able to accommodate the terahertz range.

    A few experimental technologies that have been able to convert terahertz waves into DC current do so only at ultracold temperatures — setups that would be difficult to implement in practical applications.

    Instead of turning electromagnetic waves into a DC current by applying an external electric field in a device, Isobe wondered whether, at a quantum mechanical level, a material’s own electrons could be induced to flow in one direction, in order to steer incoming terahertz waves into a DC current.

    Such a material would have to be very clean, or free of impurities, in order for the electrons in the material to flow through without scattering off irregularities in the material. Graphene, he found, was the ideal starting material.

    To direct graphene’s electrons to flow in one direction, he would have to break the material’s inherent symmetry, or what physicists call “inversion.” Normally, graphene’s electrons feel an equal force between them, meaning that any incoming energy would scatter the electrons in all directions, symmetrically. Isobe looked for ways to break graphene’s inversion and induce an asymmetric flow of electrons in response to incoming energy.

    Looking through the literature, he found that others had experimented with graphene by placing it atop a layer of boron nitride, a similar honeycomb lattice made of two types of atoms — boron and nitrogen. They found that in this arrangement, the forces between graphene’s electrons were knocked out of balance: Electrons closer to boron felt a certain force while electrons closer to nitrogen experienced a different pull. The overall effect was what physicists call “skew scattering,” in which clouds of electrons skew their motion in one direction.

    Isobe developed a systematic theoretical study of all the ways electrons in graphene might scatter in combination with an underlying substrate such as boron nitride, and how this electron scattering would affect any incoming electromagnetic waves, particularly in the terahertz frequency range.

    He found that electrons were driven by incoming terahertz waves to skew in one direction, and this skew motion generates a DC current, if graphene were relatively pure. If too many impurities did exist in graphene, they would act as obstacles in the path of electron clouds, causing these clouds to scatter in all directions, rather than moving as one.

    “With many impurities, this skewed motion just ends up oscillating, and any incoming terahertz energy is lost through this oscillation,” Isobe explains. “So we want a clean sample to effectively get a skewed motion.”

    One direction

    They also found that the stronger the incoming terahertz energy, the more of that energy a device can convert to DC current. This means that any device that converts T-rays should also include a way to concentrate those waves before they enter the device.

    With all this in mind, the researchers drew up a blueprint for a terahertz rectifier that consists of a small square of graphene that sits atop a layer of boron nitride and is sandwiched within an antenna that would collect and concentrate ambient terahertz radiation, boosting its signal enough to convert it into a DC current.

    “This would work very much like a solar cell, except for a different frequency range, to passively collect and convert ambient energy,” Fu says.

    The team has filed a patent for the new “high-frequency rectification” design, and the researchers are working with experimental physicists at MIT to develop a physical device based on their design, which should be able to work at room temperature, versus the ultracold temperatures required for previous terahertz rectifiers and detectors.

    “If a device works at room temperature, we can use it for many portable applications,” Isobe says.

    He envisions that, in the near future, terahertz rectifiers may be used, for instance, to wirelessly power implants in a patient’s body, without requiring surgery to change an implant’s batteries. Such devices could also convert ambient Wi-Fi signals to charge up personal electronics such as laptops and cellphones.

    “We are taking a quantum material with some asymmetry at the atomic scale, that can now  be utilized, which opens up a lot of possibilities,” Fu says.

    This research was funded in part by the U.S. Army Research Laboratory and the U.S. Army Research Office through the Institute for Soldier Nanotechnologies (ISN).

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