New Study On Understanding Mechanisms Of Antiviral Drugs Sheds Light of Ways to Develop Newer Anti-Resistant Drugs For HIV And Hepatitis B
A research discovery by Florida State University College of Medicine researchers is expected to open the door for new and more potent treatment options for many of the more than 45 million people worldwide infected with the HIV
virus and for others chronically ill with hepatitis B
Professor Dr Zucai Suo of the FSU College of Medicine. Credit: Colin Hackley/FSU
Their study has established for the first time the mechanism responsible for how two widely used antiviral drugs
A research paper published in Communications Biology
, an open-access journal from Nature Research, describes how Professor Dr Zucai Suo and colleagues also provide the key to understanding how a single HIV-
1 mutation can inactivate the anti-HIV drugs
emtricitabine and lamivudine. Those drugs
are worth billions in annual sales for the companies that make them, and the frequency of patients who develop resistance
creates serious and dangerous obstacles to controlling the disease.
Emtriva or emtricitabine also is approved for use in patients with hepatitis B
, which afflicts 270 million people worldwide, according to the World Health Organization.
The research paper suggests new pathways for developing drugs able to avoid specific virus mutations that can render these two blockbuster L-nucleoside drug
treatments ineffective for many patients.
It is typical for patients undergoing treatment to develop a resistance
to their prescribed anti-HIV
medications, leaving physicians with three options: adjust the treatment regimen, temporarily interrupt therapy or continue with an only partially effective regimen.
For individuals who have failed their first treatment regimen, or even a second, doctors typically try to salvage the current course of treatment by adjusting the combination of drugs
. But for patients who have failed multiple treatment regimens, there are limited options to suppress the incurable virus.
Furthermore, the number of drug
choices available when one combination fails is limited. More than a million of those infected with HIV
live in the U.S.
Dr Suo, the study's co-lead author, and an Eminent Professor and the Dorian and John Blackmon Chair in Biomedical Science at the Florida State University College of Medicine told Thailand Medical
News, “We suggest new chemical possibilities for more potent L-nucleoside
, which may possess different drug-resistance
mutation profiles from the most widely used current anti-HIV
Dr Eric Lansdon of Gilead Sciences Inc. is the co-lead author"In our paper
Dr Suo added, "Right now, there are a limited number of FDA-approved drugs available. New drugs
need to be developed if doctors are to have other options when treating so many patients who may have developed resistance
to most of the FDA-approved anti-HIV drug
The current drugs
remain highly effective in keeping the disease under control for most patients, but some patients develop a resistance
due to mutations within the HIV
Dr Suo's paper explains how the class of HIV drugs
known as L-nucleoside
reverse transcriptase inhibitors (L-NRTIs
) work. L-NRTIs
block an enzyme that HIV
needs to replicate, but they were discovered through blind trials. Important details about the underlying mechanism triggering L-NRTIs
have remained a mystery, as well as a source of controversy among the scientists who study them.
Dr Lansdon commented to Thailand Medical News,
"The enzyme has a unique pocket and supposedly recognizes NRTIs, but not their structural mirror images ie L-NRTIs
Dr Suo, had grown curious about the mechanism behind L-NRTI drugs
as a graduate student. He's been motivated since then to understand and explain the mechanism involved, which he does in his paper, one of six he has published involving L-NRTI
Dr Suo's current paper also explains how a mutation found in some patient populations leads to developing resistance
to antiviral L-NRTI drugs
Dr Suo further added, "Patients, HIV scientists and medical doctors all will benefit from this. HIV
scientists and drug c
ompanies will now know how it works and will be able to design better drugs
in the same class of medications. They will be able to build on the mechanism described in this paper to make slight adjustments for better and more powerful treatment options."
Reference : Magdeleine Hung et al, Elucidating molecular interactions of L-nucleotides with HIV-1 reverse transcriptase and mechanism of M184V-caused drug resistance, Communications Biology (2019). DOI: 10.1038/s42003-019-0706-x