August 11, 2020 | David F. Coppedge

Has COVID-19 Been Handcuffed?

A grad student and a large American team finds a molecule that puts SARS-CoV-2 into a straitjacket.

If it works, Michael Schoof, a grad student at UC San Francisco, could be a world hero. He has led a team who has found a straitjacket for the coronavirus that has infected the world. Here’s what the press release says:

Led by UCSF graduate student Michael Schoof, a team of researchers engineered a completely synthetic, production-ready molecule that straitjackets the crucial SARS-CoV-2 machinery that allows the virus to infect our cells. As reported in a new paper, now available on the preprint server bioRxiv, experiments using live virus show that the molecule is among the most potent SARS-CoV-2 antivirals yet discovered.

They’re calling it “AeroNabs” the headline says. You just inhale it once a day. Watch the video in the article to see how it works..

The SARS-CoV-2 virus, carelessly released by China, has infected millions around the world and killed tens of thousands of people so far. It has sent economies into a tailspin and put countless people out of work and companies out of business.

The UCSF team says they can make AeroNabs cheaply in industrial quantities. The molecule is stable and can be shipped around the world in powdered form. It can be made available over-the-counter and be self-administered, researchers say.

“We’re not alone in thinking that AeroNabs are a remarkable technology,” said Manglik. “Our team is in ongoing discussions with potential commercial partners who are interested in manufacturing and distributing AeroNabs, and we hope to commence human trials soon. If AeroNabs prove as effective as we anticipate, they may help reshape the course of the pandemic worldwide.”

The antibody was modeled after nanobodies in llamas and camels and then modified to bind more tightly.  (Camel: Illustra Media)

Still, it may take “a few months” for clinical trials to complete – about the same time that a vaccine may become available.

They call it “llama-inspired design” because the antibody was modified from a “nanobody” found in llamas and camels. Nanobodies have advantages over human antibodies:

For example, nanobodies are an order of magnitude smaller than human antibodies, which makes them easier to manipulate and modify in the lab. Their small size and relatively simple structure also makes them significantly more stable than the antibodies of other mammals. Plus, unlike human antibodies, nanobodies can be easily and inexpensively mass-produced: scientists insert the genes that contain the molecular blueprints to build nanobodies into E. coli or yeast, and transform these microbes into high-output nanobody factories. The same method has been used safely for decades to mass-produce insulin.

The nanobody attaches to the spike proteins on the virus so that it cannot bind to the ACE2 receptor which the virus hijacks to gain access to a human cell. The team modified the nanobody to give it an even stronger binding to the virus spike protein, putting the virus virtually into a “straitjacket.”

See also the reports by ABC News and NBC and the Federal Lab Consortium.

The team’s paper was issued as a preprint (i.e., before peer review) on bioRxiv, the biology preprint server, because of its importance. Preprints are open access for free reading without a subscription. The Abstract boasts,

These properties may enable aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia, promising to yield a widely deployable, patient-friendly prophylactic and/or early infection therapeutic agent to stem the worst pandemic in a century.

Incidentally, New Scientist announced today that a cure for one of the most common cold viruses may be available next year.

Update 9/11/2020: More support for the efficacy of these nanobodies was announced Sept 8 by Howard Hughes Medical Institute, which is working with UCSF on the project.

The work hasn’t yet been peer-reviewed, but Walter and Manglik are currently looking for partners who can produce and test the molecule for safety and efficacy in clinical trials. They hope the molecule could someday soon work as an aerosolized drug that would get directly to patients’ lungs.

Traditional antibody drugs are usually injected into the patient’s bloodstream – most antibodies fall apart when aerosolized by a nebulizer or a nasal spray, Walter says. Preliminary tests suggest that the new nanobody-based molecule is far hardier. The nanobodies kept their shape and function when sprayed, and withstood being freeze-dried and heated, too.

Aerosolized delivery of a nanobody drug “is an exciting possibility, but it hasn’t been demonstrated yet,” says Andrew Kruse, a biochemist at Harvard Medical School who has collaborated with Manglik’s team to build nanobody collections but wasn’t involved in the current study. “It would be very important to see how long an aerosol-delivered nanobody remains in the respiratory system,” he says.

Trials are usually painfully slow, but if this project gets a moonshot-like boost of funding and support, it could provide a cheap and easily-administered therapeutic that could be sold over the counter. The article mentions the inspiration provided by llamas: “It’s modeled after the simple, compact antibodies found in some animals such as llamas, alpacas, and camels.”

Update 3/09/2021: This article on Medical Xpress says that research on llama nanobodies is also progressing at the University of Texas at Austin. The article touts the benefits of this approach over vaccines, and describes how camelids produce these unique antibodies that are about half the size of human antibodies. This makes them more compact for binding to the viral spike proteins. They are also long-lasting, .

I saw the preprint on bioRxiv earlier today and it sounded too good to be true. Now that UCSF is standing behind it and announcing it in a press release, we wanted to be among the first to share the news.

Perhaps clinical trials can be rushed, or people can use it under the “Right to Try” laws before it is officially approved by the FDA.

The Russians are claiming to have released the first vaccine, but people have their doubts if Russia has followed reliable protocols. Even when vaccines arrive, AeroNabs may be useful as protection from the virus in many situations, since they are cheap and can be self-administered.

It’s nice to see science used to solve big problems, and to see human ingenuity at work. And thank you camels for donating your antibodies!



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