The emergence of severe acute respiratory syndrome coronavirus type 2 (novel coronavirus) led to the outbreak of coronavirus disease (coronavirus pneumonia-19), which has evolved into a serious global public health crisis. Redixivir is the most advanced antiviral drug currently used in the treatment of coronavirus pneumonia-19. In the United States, it has been approved for the emergency of critically ill patients, but its mortality benefit has not been confirmed.
Coronavirus pneumonia-19 The early clinical manifestation is severe viral pneumonia. The new data clearly show that novel coronavirus directly or indirectly caused great damage to other organ systems through downstream immune effects. Up to 75% of patients with coronavirus pneumonia-19 showed renal involvement to some extent, and a large number of them had acute renal injury. Acute respiratory distress syndrome (ARDS) is a common and fatal manifestation of coronavirus pneumonia-19, which is related to long-term intubation and high mortality.
A new drug development method is to focus on the affected host cells, rather than on pathogens. Inspired by the fact that novel coronavirus's infectivity depends on its binding to known or unknown protein receptors on target cells, we created a cell nano sponge as a medical countermeasure for coronavirus. These nano sponge are made of membranes derived from human cells, which are derived from natural targeted cells in novel coronavirus (figure 1).
Novel coronavirus used angiotensin-converting enzyme 2(ACE2) and CD 147 to express host cells (such as human alveolar epithelial type II cells) as receptors for cell entry. Human macrophages all express CD 147. It is reported that they frequently interact with virus-targeted cells through chemokines and phagocyte signaling pathways, and play an important role in human infection.
In laboratory experiments, both lung sponge and immune cell nano sponge made novel coronavirus virus lose nearly 90% of its "viral infectivity" in a dose-dependent manner. (Source: David Bailote/University of California at San Diego)
Manufacture and test of coronavirus pneumonia-19 nano sponge.
Each coronavirus pneumonia-19 nano sponge-is smaller than the width of human hair by 1000 times, and consists of a polymer core wrapped with a cell membrane extracted from lung epithelial type II cells or macrophages. These spongy membranes contain the same protein receptors as the cells they mimic, including any receptors that novel coronavirus uses to enter cells in vivo.
The researchers prepared several different concentrations of nano sponge solution to test novel coronavirus. In order to test nano sponge's ability to prevent novel coronavirus infection, researchers from the University of San Diego turned to the team of National Laboratory for Emerging Infectious Diseases (NEIDL) of Boston University for independent testing.
In this BSL-4 laboratory, researchers led by Anthony Griffiths, an associate professor of microbiology at Boston University School of Medicine, tested the ability of each concentration of nano sponge to reduce its infectivity. Novel coronavirus live virus-the same strain tested in the treatment and vaccine research of other coronavirus pneumonia-19.
When the concentration was 5 mg/ml, the infection inhibition rate of sponge wrapped on lung cell membrane was 93%. The sponge covered with macrophages inhibited the infectivity of novel coronavirus virus by 88%. Viral infectivity refers to the ability of a virus to enter a host cell and use its resources to replicate and produce additional infectious virus particles.
In the next few months, researchers and collaborators at the University of California, San Diego will evaluate the efficacy of nano sponge in animal models. A team from the University of California, San Diego, has demonstrated the short-term safety of mice's respiratory tract and lungs. Whether and when these coronavirus pneumonia-19 nano sponge will be tested in humans depends on many factors, but researchers are taking action as soon as possible. The researchers also predict that these nano sponge will fight against any novel coronavirus and even other respiratory viruses, including any virus that may cause the next respiratory epidemic.
Simulated lung epithelial cells and immune cells
Novel coronavirus often infects lung epithelial cells, which is the first step of coronavirus pneumonia-19 infection. Therefore, Zhang and his colleagues think it is necessary to cover up the nanoparticles in the outer membrane fragments of lung epithelial cells to see if the virus can be deceived by lung cells rather than attached to them.
Macrophages are white blood cells, which play an important role in inflammation. During the-19 disease, it was also very active in the lungs, so Zhang and his colleagues created another kind of nano sponge covering the macrophage membrane. The research team plans to study whether macrophage sponge can also calm the cytokine storm in patients with coronavirus pneumonia-19.
Zhang warned that 19 nano sponge platform had already carried out a major test on it, and only then did scientists know that it would be a safe and effective human virus therapy. However, if the sponge reaches the clinical trial stage, there are many potential treatment methods, including intubation of patients (such as asthma patients) and direct delivery to the lungs through inhalers or veins, especially for the treatment of complications of cytokine storms.
Schematic diagram of cell nano sponge inhibiting novel coronavirus infectivity. (Source: doi:10.1021/acs.nanolett.0c02278)
Nano sponge's growth momentum
Ten years ago, Zhang created the first membrane-coated nanoparticles in the laboratory of the University of California, San Diego. The first layer of these nano sponge is covered with fragments of erythrocyte membrane. These nano sponge are being developed for the treatment of bacterial pneumonia, and all stages of preclinical testing are conducted by Cellics Therapeutics (Zhang * * *, a startup company in San Diego).
At present, the company is submitting an application for an investigational new drug (IND) to its new drug candidate (FDA): red blood cell nano sponge, which is used to treat MRSA pneumonia. The company estimates that the first batch of patients in clinical trials will receive treatment next year.
Researchers at the University of California, San Diego have also shown that nano sponge can deliver drugs to the wound site. Absorb bacterial toxins that cause septicemia; And intercept HIV infection of human T cells.
The basic structure of these nano sponge is the same: the biodegradable, FDA-approved polymer core is wrapped in a specific type of cell membrane, so it may be disguised as red blood cells, immune T cells or platelet cells. Camouflage can prevent the immune system from finding and attacking dangerous intruders.
Zhang said, I think cell membrane fragments are effective components. This is another way to study drug development. For coronavirus pneumonia-19, I hope other teams can come up with safe and effective treatments and vaccines as soon as possible. At the same time, we are working hard and planning, as if the whole world is counting on us.