Four research teams at Columbia University will share a $2.1 million grant to mount an aggressive effort to identify potential antiviral drugs and antibodies for use against the new coronavirus, 2019-nCoV. The funding was awarded by the Jack Ma Foundation, based in Hangzhou City, Zhejiang Province, China. As part of the project, the Columbia scientists will collaborate with academic researchers in China who are fighting to control the outbreak.
The Columbia teams will pursue four different approaches to develop drugs or antibodies that prevent the virus from replicating. Each approach will draw on prior knowledge and expertise the scientists gained while working on successful antiviral therapies against HIV and hepatitis C.
If administered before an infection takes place, such a drug or antibody could confer protection against infection by 2019-nCoV. In individuals who are already infected, an effective antiviral drug or antibody could block the continued growth of the virus in patients who are seriously ill.
The Columbia effort is being led by David D. Ho, MD, founding scientific director of the Aaron Diamond AIDS Research Center and professor of medicine at Columbia. Three of the Columbia teams are in the Vagelos College of Physicians and Surgeons, and the fourth is in the School of Engineering and Applied Sciences.
The Columbia teams will pursue projects aimed at identifying or developing two types of antiviral drugs and one type of virus-neutralizing antibody:
Protease inhibitors
Viruses rely on enzymes, called proteases, to allow them to cut their larger proteins into smaller and proper components in order to replicate. Drugs that inhibit the activity of proteases have been used with tremendous success to treat HIV and hepatitis C. A team led by Alex Chavez, MD, PhD will use a new drug screening approach to rapidly screen a large number of compounds that block the protease of 2019-nCoV. His team, in conjunction with Dr. Ho, will attempt to select a handful of positive hits to develop into drug candidates, with the goal of advancing at least one compound into clinical trials.
Polymerase inhibitors
In order for coronaviruses to copy their RNA and replicate, they rely on a crucial enzyme called polymerase. A Columbia team led by Stephen Goff, PhD, and Yosef Sabo, PhD, will produce large quantities this enzyme and then screen hundreds of thousands of chemical compounds to identify ones that inhibit the function of the enzyme and thereby block replication of the virus. The most promising ones will, again, be selected as drug candidates for treatment or prevention of 2019-nCoV.
Jingyue Ju, PhD, and his team will pursue a different approach to inhibit the function of polymerase in the virus. They have observed that hepatitis C and coronaviruses use a similar mechanism to replicate their RNA. They believe that a currently approved antiviral drug, Sofosbuvir, which is used to treat hepatitis C, may also be effective against 2019-nCoV. This drug, part of a new class of drugs called nucleotide analogues, inhibits the polymerase enzyme of hepatitis C and thus blocks its replication. Ju and his team will utilize their expertise in synthetic chemistry to generate many more such chemical compounds for testing in collaboration with Drs. Ho, Goff, and Sabo. Best chemical compounds that specifically inhibit 2019-nCoV polymerase will be chosen as drug candidates.
Monoclonal antibodies
Dr. Ho will lead an effort aimed at developing monoclonal antibodies – molecules that can bind to the surface of the coronavirus and neutralize the infectivity of the virus. His team will try to isolate antibodies from blood cells of patients who no longer have the virus and have recovered from 2019-nCoV infection. Then they will engineer the virus-neutralizing antibodies further to optimize their potency against 2019-nCoV. The most promising antibodies will be sent to collaborating labs in China where they will be tested against actual coronavirus in the lab as well as in animal models.
“Over the past two decades we’ve seen the emergence of three deadly coronaviruses – SARS, MERS, and now 2019-nCoV,” said Ho. “We believe it is likely that new coronaviruses will emerge in the future. The four projects we are now pursuing against 2019-nCoV were chosen because we believe they will lead to the development of a broad spectrum antiviral drug or antibody that could be effective against a wide range of current and future coronaviruses.”
“We’re undertaking this work with a great sense of urgency because of the nature of the current coronavirus outbreak,” Ho added, “but we are also thinking ahead to what we may confront in the future.”
Ho said that the Columbia teams expect to move at least one protease inhibitor, one polymerase inhibitor, and one monoclonal antibody into clinical trials within a year.
“We are deeply grateful to the Jack Ma Foundation for their partnership and support as our scientists work to tame a contagion that has rapidly become a global threat,” said Ho.
