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Tweaking the chemical makeup of hydroxychloroquine beyond COVID-19

Researchers are still evaluating the utility of hydroxychloroquine for treatment or prevention of COVID-19, but it still has well documented use in helping millions of people around the world manage some autoimmune diseases such as lupus and rheumatoid arthritis. 
West Virginia University researchers Mark McLaughlin and Gabriel Garcia are exploring how tiny changes to the molecular structures of hydroxychloroquine and its predecessor, chloroquine, can improve the drugs’ performance and reduce their side effects for patients prescribed the drugs for a variety of conditions. 
Their project focuses on analogs to hydroxychloroquine and chloroquine. An analog is a chemical compound with a molecular structure that’s similar to—but not a duplicate of—another drug. They resemble each other the way two cousins might, rather than how identical twins do.
“Hydroxychloroquine has been an FDA-approved drug for 70 years or so, and chloroquine was approved even earlier,” said McLaughlin, a professor of medicinal chemistry in the School of Pharmacy and a member of the Cancer Institute. “When chloroquine was established as a drug, it was during the very early understanding of how medicinal chemistry works. There weren’t a lot of analogs tested, unlike the normal methodology for developing drugs today.”
McLaughlin, Garcia and their colleagues have made six of the nine analogs they originally planned to create.
“And since then, we’ve come up with additional analogs that we think could be important,” McLaughlin said.
The researchers are subjecting these new analogs to laboratory testing so they can learn how the human body would absorb them, distribute them through the bloodstream, metabolize them and excrete them. Insights into these four properties—commonly abbreviated as “ADME”—underpin drug discovery. 
Modifying two existing medications instead of starting from scratch is “better than total guesswork, even if you get just a hint of activity,” McLaughlin said. “Then you can take that molecule, modify it and see what it targets when you test it. And you do the same thing again and again and again, until you get something good.”
Could these analogs provide meaningful improvements?
In 2017 alone, doctors across the nation wrote five million prescriptions for hydroxychloroquine. That doesn’t even take chloroquine prescriptions into account.
“When that many people are treated for that long a period of time, there will often be a segment of the population that will develop side effects,” McLaughlin said. “And almost any drug that’s considered safe and effective actually has a bad effect on some small proportion of people.”
Even minor side effects can vex someone who takes a drug every day for 20 or 30 years.
But what McLaughlin and his team discover may go beyond autoimmune diseases. Hydroxychloroquine and chloroquine are used in other applications as well, including cancer treatment.
“Dr. McLaughlin’s work is critically important, as developing more potent and safer alternatives that preserve the many mechanisms through which the drug functions would allow us to treat cancer patients safely, improve their response to treatment and ultimately improve their outcome,” said Brian Boone, an assistant professor in the School of Medicine and a surgeon with WVU Medicine.
Boone has been studying the use of chloroquine to improve outcomes in pancreatic cancer patients for years. It was his research—not the COVID-19 pandemic—that inspired McLaughlin to look into chloroquine and hydroxychloroquine himself.
“Actually, I got interested in this because Brian Boone gave a talk about it about three weeks before any interest in hydroxychloroquine was expressed by Trump,” McLaughlin said.
The results of this research may influence how doctors treat a range of diseases long after the COVID-19 pandemic has ended. Because even after COVID-19 cases have abated—and even if a coronavirus vaccine has been developed and deployed—millions of people will still be diagnosed with cancers and chronic autoimmune conditions. 
And they’ll need treatment options, too.