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Seaweed extract outperforms remdesivir in inhibiting SARS-CoV-2 in cell studies

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In a test of antiviral effectiveness against the virus that causes COVID-19, an extract from edible seaweeds substantially outperformed remdesivir, the current standard antiviral used to combat the disease. Heparin, a common blood thinner, and a heparin variant stripped of its anticoagulant properties, performed on par with remdesivir in inhibiting SARS-CoV-2 infection in mammalian cells.

Published online today in Cell Discovery, the research is the latest example of a decoy strategy researchers from the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselear Polytechnic Institute are developing against viruses like the novel coronavirus that spawned the current global health crisis.

The spike protein on the surface of SARS-CoV-2 latches onto the ACE-2 receptor, a molecule on the surface of human cells. Once secured, the virus inserts its own genetic material into the cell, hijacking the cellular machinery to produce replica viruses. But the virus could just as easily be persuaded to lock onto a decoy molecule that offers a similar fit. The neutralized virus would be trapped and eventually degrade naturally.

Previous research has shown this decoy technique works in trapping other viruses, including dengue, Zika, and influenza A. To hear the researchers discuss their findings, watch this video.

We’re learning how to block viral infection, and that is knowledge we are going to need if we want to rapidly confront pandemics. The reality is that we don’t have great antivirals. To protect ourselves against future pandemics, we are going to need an arsenal of approaches that we can quickly adapt to emerging viruses.”

Jonathan Dordick, lead researcher and a professor of chemical and biological engineering at Rensselaer Polytechnic Institute

The Cell Discovery paper tests antiviral activity in three variants of heparin (heparin, trisulfated heparin, and a non-anticoagulant low molecular weight heparin) and two fucoidans (RPI-27 and RPI-28) extracted from seaweed. All five compounds are long chains of sugar molecules known as sulfated polysaccharides, a structural conformation that the results of a binding study published earlier this month in Antiviral Research suggested as an effective decoy.

The researchers performed a dose response study known as an EC50 — shorthand for the effective concentration of the compound that inhibits 50% of viral infectivity — with each of the five compounds on mammalian cells. For the results of an EC50, which are given in a molar concentration, a lower value signals a more potent compound.

RPI-27 yielded an EC50 value of approximately 83 nanomolar, while a similar previously published and independent in vitro test of remdesivir on the same mammalian cells yielded an EC50 of 770 nanomolar. Heparin yielded an EC50 of 2.1 micromolar, or about one-third as active as remdesivir, and a non-anticoagulant analog of heparin yielded an EC50 of 5.0 micromolar, about one-fifth as active as remdesivir.

A separate test found no cellular toxicity in any of the compounds, even at the highest concentrations tested.

“What interests us is a new way of getting at infection,” said Robert Linhardt, a Rensselaer professor of chemistry and chemical biology who is collaborating with Dordick to develop the decoy strategy. “The current thinking is that the COVID-19 infection starts in the nose, and either of these substances could be the basis for a nasal spray. If you could simply treat the infection early, or even treat before you have the infection, you would have a way of blocking it before it enters the body.”

Dordick added that compounds from seaweed “could serve as a basis for an oral delivery approach to address potential gastrointestinal infection.”

In studying SARS-CoV-2 sequencing data, Dordick and Linhardt recognized several motifs on the structure of the spike protein that promised a fit compatible with heparin, a result borne out in the binding study. The spike protein is heavily encrusted in glycans, an adaptation that protects it from human enzymes which could degrade it, and prepares it to bind with a specific receptor on the cell surface.

“It’s a very complicated mechanism that we quite frankly don’t know all the details about, but we’re getting more information,” said Dordick. “One thing that’s become clear with this study is that the larger the molecule, the better the fit. The more successful compounds are the larger sulfated polysaccharides that offer a greater number of sites on the molecules to trap the virus.”

Molecular modeling based on the binding study revealed sites on the spike protein where the heparin was able to interact, raising the prospects for similar sulfated polysaccharides.

“This exciting research by Professors Dordick and Linhardt is among several ongoing research efforts at CBIS, as well as elsewhere at Rensselaer, to tackle the challenges of the COVID-19 pandemic through novel therapeutic approaches and the repurposing of existing drugs,” said CBIS Director Deepak Vashishth.

“Sulfated polysaccharides effectively inhibit SARS-CoV-2 in vitro” was published in Cell Discovery with the support of the National Research Foundation of Korea. At Rensselaer, Dordick and Linhardt were joined in the research by Paul S. Kwon, Seok-Joon Kwon, Weihua Jin, Fuming Zhang, and Keith Fraser, and by researchers at the Korea Research Institute of Bioscience and Biotechnology in Cheongju, Republic of Korea, and Zhejiang University of Technology in Hangzhou, China.

Journal reference:

Kwon, P.S., et al. (2020) Sulfated polysaccharides effectively inhibit SARS-CoV-2 in vitro. Cell Discovery. doi.org/10.1038/s41421-020-00192-8.

Source: https://www.news-medical.net/news/20200724/Seaweed-extract-outperforms-remdesivir-in-inhibiting-SARS-CoV-2-in-cell-studies.aspx

Biotechnology

Perceptive debuts LianBio with cancer and heart disease programs from BridgeBio, MyoKardia

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After working in stealth since October, Perceptive Advisors is unveiling its latest biotech: LianBio, which serves the dual mission of bringing much-needed new drugs to China and helping U.S. biotech companies expand their operations into Asia.

LianBio launches with a trio of assets licensed from MyoKardia and BridgeBio Pharma companies Navire Pharma and QED Therapeutics. LianBio is handing over more than $60 million upfront in exchange for development and commercialization rights to the programs in China and “selected Asian markets.” BridgeBio and MyoKardia will pick up equity in the LianBio, too.

And that’s not all—LianBio has a “strategic relationship” with BridgeBio that gives it first dibs on the 20 programs already in the latter’s pipeline, as well as any assets it may bring under its umbrella in the next four years, said Konstantin Poukalov, a managing director at Perceptive Advisors and executive chairman of LianBio. The company will be on the hook for up to $505 million in milestone payments to BridgeBio and $147.5 million to MyoKardia.

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LianBio’s pipeline includes mavacamten—a treatment for hypertrophic cardiomyopathy (HCM), an inherited disorder that causes the muscle walls of the heart to thicken, potentially to the point where they can obscure blood flow. MyoKardia plans to submit the drug for FDA approval for obstructive HCM in early 2021 and continue to develop it for patients with the non-obstructive form of HCM and those with a specific kind of heart failure, in which the left ventricle can’t properly fill with blood and pumps less blood to the body than normal.

RELATED: GlaxoSmithKline veteran Zhi Hong launches Brii Biosciences with $260M

LianBio has also licensed infigratinib, QED Therapeutics’ EGFR inhibitor that’s in a phase 3 study for bile duct cancer, and a SHP2 inhibitor that Navire Pharma is developing for drug-resistant tumors and other hard-to-treat cancers. LianBio hands over $26.5 million upfront

The company views these as more than just licensing deals, Debra Yu, LianBio’s chief business officer said. It plans to pitch in and run clinical trials in China and other parts of Asia where appropriate.

“It isn’t just like we get mavacamten and we go wherever we want with it and pay them the royalties,” Yu said.

“In the case of mavacamten, MyoKardia already got it all the way through for the obstructive HCM indication and we’ll take it into China,” she added. “But for the other indications, in nonobstructive HCM and (heart failure with preserved ejection fraction), we will work side by side with them.”

As for infigratinib, that could mean testing the drug in cancers that QED is not yet looking at, but that are prevalent in China, such as gastric cancer, she added.

It’s part of Perceptive and LianBio’s bid to bring cutting-edge medicines to China and address what CEO Bing Li calls the gap between global innovation and the China market.

“China has predominantly been a generics market for most of its time,” Yu said. “Even today, there is still a very limited number of innovative drugs and certainly not those we would call ‘paradigm-shifting.”

As it advances its pipeline, LianBio aims to double its team by the end of the year. It will be on the hunt for more assets that it might want to pursue in China, both through its deal with BridgeBio and other potential partners.

When asked if LianBio would ever dive into in-house discovery and development, Poukalov said “nothing is ever off the table,” but that the core focus of the company’s model is “high-quality assets that are highly significantly derisked.”

“But once our therapeutic areas of focus are established, we are certainly willing to move to earlier stages of development,” Poukalov added. That could include putting together novel cancer-fighting combinations based on Navire’s SHP2 inhibitor.

“In the near-term, I don’t think we are going to be doing true benchwork—there are plenty of people who are good at doing that—but we will be utilizing what we know and the access we have to be creative and do early-stage development work,” he said.

Editor’s note: This story has been updated to remove the dollar amount of LianBio’s funding as it was incorrect.

Source: https://www.fiercebiotech.com/biotech/perceptive-debuts-lianbio-cancer-and-heart-disease-programs-from-bridgebio-myokardia

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SMART research enhances dengue vaccination in mice

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Researchers from the Singapore-MIT Alliance for Research and Technology (SMART), MIT’s research enterprise in Singapore, have found a practical way to induce a strong and broad immunity to the dengue virus based on proof-of-concept studies in mice. Dengue is a mosquito-borne viral disease with an estimated 100 million symptomatic infections every year. It is endemic in over 100 countries in the world, from the United States to Africa and wide swathes of Asia. In Singapore, over 1,700 dengue new cases were reported recently. 

The study is reported in a paper titled “Sequential immunization induces strong and broad immunity against all four dengue virus serotypes,” published in NPJ Vaccines. It is jointly published by SMART researchers Jue Hou, Shubham Shrivastava, Hooi Linn Loo, Lan Hiong Wong, Eng Eong Ooi, and Jianzhu Chen from SMART’s Infectious Diseases and Antimicrobial Resistance (AMR) interdisciplinary research groups (IRGs). 

The dengue virus (DENV) consists of four antigenically distinct serotypes and there is no lasting immunity following infection with any of the DENV serotypes, meaning someone can be infected again by any of the remaining three variants of DENVs.

Today, Dengvaxia is the only vaccine available to combat dengue. It consists of four variant dengue antigens, one for each of the four serotypes of dengue, expressed from attenuated yellow-fever virus. The current three doses of immunization with the tetravalent vaccine induce only suboptimal protection against DENV1 and DENV2. Furthermore, in people who have not been infected by dengue, the vaccine induces a more severe dengue infection in the future. Therefore, in most of the world, the vaccination is only given to those who have been previously infected. 

To help overcome these issues, SMART researchers tested on mice whether sequential immunization (or one serotype per dose) induces stronger and broader immunity against four DENV serotypes than tetravalent-formulated immunization — and found that sequential immunization induced significantly higher levels of virus-specific T cell responses than tetravalent immunization. Moreover, sequential immunization induced higher levels of neutralizing antibodies to all four DENV serotypes than tetravalent vaccination.

“The principle of sequential immunization generally aligns with the reality for individuals living in dengue-endemic areas, whose immune responses may become protective after multiple heterotypic exposures,” says Professor Eng Eong Ooi, SMART AMR principal investigator and senior author of the study. “We were able to find a similar effect based on the use of sequential immunization, which will pave the way for a safe and effective use of the vaccine and to combat the virus.”

Upon these promising results, the investigators will aim to test the sequential immunization in humans in the near future.

The work was supported by the National Research Foundation (NRF) Singapore through the SMART Infectious Disease Research Program and AMR IRG. SMART was established by MIT in partnership with the NRF Singapore in 2007. SMART is the first entity in the Campus for Research Excellence and Technological Enterprise (CREATE) developed by NRF.  SMART serves as an intellectual and innovation hub for research interactions between MIT and Singapore, performing cutting-edge research of interest to both Singapore and MIT. SMART currently comprises an Innovation Centre and five IRGs: AMR, Critical Analytics for Manufacturing Personalized-Medicine, Disruptive and Sustainable Technologies for Agricultural Precision, Future Urban Mobility, and Low Energy Electronic Systems. SMART research is funded by the NRF Singapore under the CREATE program.  

The AMR IRG is a translational research and entrepreneurship program that tackles the growing threat of antimicrobial resistance. By leveraging talent and convergent technologies across Singapore and MIT, they aim to tackle AMR head-on by developing multiple innovative and disruptive approaches to identify, respond to, and treat drug-resistant microbial infections. Through strong scientific and clinical collaborations, they provide transformative, holistic solutions for Singapore and the world.


Source: http://news.mit.edu/2020/smart-researchers-enhance-dengue-vaccination-mice-0811

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Medtronic snaps up smart insulin pen maker Companion Medical in a ‘bold move’

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Medtronic is buying up leading smart insulin pen and phone app maker Companion Medical as it looks to shore up its growing weakness in the pump market.

The med tech major gets access to Companion’s InPen, a so-called smart insulin pen that not only delivers insulin, but also tracks insulin on board, provides an meal bolus calculator and shares information with connected systems.

The InPen last for around a year and works with short-acting insulins, although work is being done on long-acting insulins. The company made around $11 million in 2019 sales and was looking to triple that this year, after launching in late 2017, though its market penetration is pretty low.

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“This acquisition is an ideal strategic fit for Medtronic as we further simplify diabetes management and improve outcomes by optimizing dosing decisions for the large number of people using multiple daily injection (MDI),” said Sean Salmon, EVP and president of the Diabetes Group at Medtronic.

“We look forward to building upon the success of the InPen by combining it with our intelligent algorithms to deliver proactive dosing advice personalized to each individual. This smart CGM system can help people think less about diabetes and be able to live life with more freedom, on their own terms.

”Our goal is to become a trusted partner that offers consistent support whether an individual wants to stay on MDI, transition to automated insulin delivery or take a break from their pump.”

Analysts at Jefferies said the buyout was a “bold move” and a “source of growth” for Medtronic, and could add $200 million in incremental revenue.  

It points out that Medtronic has “been floundering in diabetes,” losing around a point of share a month in the pump market. The Companion deal will help offset this, and allows Medtronic to serve not only the current and future pump market, but also those that chose to stay on pens, Jefferies said in a note the clients.

The plan now is to combine its diabetes tools (from its Nutriono and Klue buyouts) with InPen and integrate its own continuous glucose monitoring (CGM) system.

Jefferies notes however that the future of insulin delivery “remains a debate.” They firm muses whether smart pens “provide enough of a clinical leap for patients such that pumps prove too much of a relative burden for their benefits.”

Financial details of the deal were not made public. Medtronic’s shares were up nearly 2% Tuesday.

Source: https://www.fiercebiotech.com/medtech/medtronic-snaps-up-smart-insulin-pen-maker-companion-medical-a-bold-move

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