The New Yorker April 13, 2020 pp16-22 DEPT. OF SCIENCE “ATTACK MODE” “Can we create antivirals to combat the next pandemic?” By Mathew Hutson
“With each new virus, we’ve scramble for a new treatment. Our approach has been ‘one bug, one drug’”
1994-HIV, Human Immunodeficiency Virus AKA the AIDs Virus-A RNA virus. David “Ho found that a certain class of drugs could dramatically reduce the viral load of AIDS patients”. But RNA viruses, of all microbes, are especially able to rapidly become resistant by mutating. So, Ho’s team developed an “an ‘AIDs Cocktail’” consisting for four drugs that reduced HIV's ability to evade therapy.
SARS-CoV, a coronavirus, causing a Severe Acute Respiratory Syndrome emerged in China November 2002 but was contained and ended in July 2003.
“Another coronavirus, MERS-CoV, caused an outbreak in the Arabian Peninsula; Middle East respiratory syndrome” in 2012 but “passed quickly”.
SARS-CoV-2 or COVID-19, another coronavirus, in China on or before December 2019 has, as we are all aware, become a pandemic that won't end until there is sufficient herd immunity and ultimatlely an effective vaccine if one can be developed. HIV and HCV are examples of viruses without an effective vaccine.
As it turns out, acute viral syndromes that resolve rapidly and without much mortality are not profitable pursuits for biopharma and are not funded by government-research grants. COVID-19 given its global spread and mortality has gotten everyone’s attention and funding is being provided.
History of anti-microbial treatments.
In some cases, the route of transmission is such that education, changes in sanitation and certain precautions can limit the spread of microbial disease. Most bacteria don’t mutate rapidly and many antibiotics have been successful as treatments. Protozoa, like Malaria are spread by mosquitos and fleas but are restricted by “climate and geography” and public control measures can help like treating mosquito breading grounds with insecticides.
Viruses, especially RNA, are problematic because they mutate rapidly, can be spread by the respiratory route and some are infectious when the carrier is without signs or symptoms of disease. These viruses originate in animals but sometimes cross species and become capable of infecting humans by animal to human transmission and then proliferate further by human-to-human transmission. Some public health measures like frequent hand-washing and physical distancing can reduce the spread of a new virus. When a new pathogenic virus emerges the population is at risk because no innate immunity or vaccine exists. Effective vaccines, if they can be developed, boost immune defenses by stimulating the production of viral neutralizing antibodies that target the virus for elimination by host defenses. They are proactive treatments but can only be created after our exposure and thorough scientific research and development. Vaccines are typically very specific and designed to meet this year’s form of the virus when the virus is the type, like RNA viruses (includes influenza and coronavirus), that mutates rapidly.
“For the roughly two hundred identified viruses…there are approved treatments for only ten or so”. Unlike antibiotics, that act on classes of bacteria, current anti-viral drugs are typically effective only on one virus. The approach, in the past has been, "one bug, one drug". So, knowing these limitations and understanding the unparalled mortality of the Spanish Flu (1918) and COVID-19 (2019), the search is now on for “one pill, or, anyway, a mere handful-that will eliminate whatever ails us”.
The New Approach
New anti-viral drugs will target based on a detailed understanding viral pathogenesis. If you will understanding “soup-to-nuts” how different viruses reproduce by co-opting bacterial and human host cells. Viruses consist of nucleic acid (RNA or DNA) encased in a protein and or a protein and lipid coating. The virus or viral particles infect cells and then reproduce by usurping the cellular machinery to replicate their nucleic acid (genes), their viral coat and then assemble and release thousands of new viral particles. The viral mechanism involves, enzymes that shuttle viruses into and out of cellular targets, nucleic acid polymerases (make strings of RNA from precursors), proteases (chop up strings of new proteins into active elements), and precursor building blocks for nucleic acids known as nucleotide and nucleosides. Unfortunately, these systems are necessary for mammalian/human cell function as well. So the trick is finding therapies that preferentially stop the virus from replicating without harming the host cell. These drugs need to preferentially inhibit viral proteases, viral polymerases, shuttling enzymes or be faulty nucleotides without overly affecting the host cell. At this point in time, given new computing capabilities and better understanding of molecular biology, researchers can modernize the search for broadly-reactive anti-virals by systematically evaluating thousands of potential drugs. Once, such drugs are created, if not viable for biopharma, then government health agencies will have to create and maintain stockpiles for the inevitable next pandemic.