One of my old research lab mates sent me a video clip in early April about an Italian female biochemist answering a question of why there was still no treatment for this viral disease. She said on the video that she got 40,000 dollars as a postdoc and the nation should ask their beloved soccer players who earn millions of dollars a year to find the cure. All I think is I didn’t even earn that much as a postdoc, no wonder I couldn’t find a cure. Joke aside, I believe there are definitely issues of our current research institutes, but that is not what I mean to talk about here. There are still many things we don’t know about this virus, such as the details of this virus tackling our innate immune response, so they could replicate fast at the early infectious stage. But we also do know quite a lot of this virus in a rather short of time, such as the full genome sequence was available as early as January 11 less than a week that the Chinese health authority and WHO announced the discovery of the SARS-CoV-2. Many years of fundamental research on human or nonhuman coronavirus also give us the knowledge to base on in developing and/or trying many antiviral approaches. Here are some famous and maybe not so famous ones.
Topic 2: Antiviral targeting on the viral entry-the early pathway
Every step of the viral replication cycle could be a potential target for antiviral strategy. So why don’t we start with the viral entry, since it was the topic from the last one anyway? You probably already known because you were too bored at home to read my viral blog topic 1, that SARS-CoV-19 needs an anchor to hook on the cell surface before the infusion. The bait the SARS coronaviruses (1 & 2) using in this process is called the S protein, Spike protein, while the cell anchor is the protein called ACE2. Now, if we try to interfere with the interaction between those two to prevent the viral infection, one thing we could do is producing many “fake anchors”, neutralizing antibodies, which will stick to S protein on its active bonding site and end the nightmare before it even gets started. The expert in making those antibodies is our own immune system. But the problem is you need to be infected to produce them or get them from a SARS-CoV-2 survivor’s blood, which is known as convalescent plasma. Some of the antibodies from the SARS-CoV-1 patients also show inhibition of SARS-CoV-2 entry, but with low efficiency even though both S proteins were designed to aim ACE2 receptor and that means antibodies have a very narrow spectrum in treating of viral infections. So it won’t be surprising that they might have no effect on future coronavirus infections, CoV-22 or CoV-25. Rabbit sera after SARS-CoV-1 infection, would reduce both SARS coronavirus entry with high efficiency, but it needs to be humanized (make it more like a human antibody to avoid unnecessary immune response) before considering it as a treatment.
Another clever way to stop the virus at the gate is to target an essential protein at the early entry pathway. As we mentioned last time, S protein needs to be “trimmed” to induce the fusion between viral and cellular membranes. The job is done by not a viral, but a membrane bonded cellular protein called TMPRSS2 (transmembrane protease/serine subfamily member 2). Finding a protease inhibitor, more precisely a serine protease inhibitor would probably get the job done. In 2012 a group of scientists from Japan and Netherlands proved the concept of Camostat mesylate, a serine protease could prevent SARS-CoV-1 entry, and later in 2013 same Japanese group proved the same compound could also prevent MERS viral entry. The significance of these findings not only shows both SARS-CoV-1 and MERS are largely depending on TMPRSS2 for the viral entry regardless of their receptor differences but also, gives us a drug candidate, which is so ready to go. (Camostat mesylate is approved in Japan for the treatment of chronic pancreatitis.) And no surprise, a new study trying the camstat mesylate on SARS-CoV-2 has soon been done and published on Cell on April 16th, 2020, by a German research group. The results are positive and encouraging, so encouraging that only one month after, researchers at Aarhus University in Denmark will start a clinical trial. One thing worth mentioning for the Cell paper is the assay was done by using the live SARS-CoV-2 virus in Calu-3, a human lung cancer cell line. That is as close as you can get to mimic the life scenario in vitro and that may give the developer the confidence to jump into the pricy clinical trial. It was the part of the story reported in a Science article titled “These drugs don’t target the coronavirus-they target us”. Another part of the story in the article was about a ongoing work led by the University of California, San Francisco. Simply speaking, they are using marked viral proteins to fish out all the cellular proteins they attached to during the viral replication. the purpose is looking for all the possible targets of host cellular proteins. They started the project from January 24th, 2020, and “produced the last bits of data a few hours before the university shut down on March 18th”.So far, they have fished out 332 human proteins that involve in the viral life circle. When I read this, I have a bit of bitter and sweet feelings in my heart. I still remember all the criticisms and doubts about our unfounded proposals, semester presentations, or academic meetings in the past years questioning us for choosing a cellular enzyme as a viral target.