Very potent antiviral against dengue
The antiviral is exceptionally effective against all known dengue
variants and could also be used for prevention purposes.

Date:
October 6, 2021
Source:
KU Leuven
Summary:
Researchers have developed an ultrapotent inhibitor of the dengue
virus, which causes the tropical disease known as dengue. The
antiviral molecule is exceptionally effective against all known
dengue variants and could be used for therapeutic and prevention
purposes.



FULL STORY ========================================================================== Researchers at the KU Leuven Rega Institute and CD3 have developed an ultrapotent inhibitor of the dengue virus, which causes the tropical
disease known as dengue. The teams collaborated closely with Janssen Pharmaceutica, N.V. The antiviral molecule is exceptionally effective
against all known dengue variants and could be used for therapeutic and prevention purposes. The teams have published their findings in Nature.


==========================================================================
Each year, dengue infects up to 400 million people, sickens up to 100
million, and kills thousands. Symptoms of the disease include a high
fever and severe muscle and joint pain. Some patients also suffer from subcutaneous bleeding or capillary leakage.

The disease is caused by the mosquito-borne dengue virus, which is found
in nearly all (sub)tropical regions, but especially in Latin America
and Asia. The frequency of outbreaks continues to grow, and the virus
is expected to impact billions more in the coming decades as the virus
spreads to other regions due to climate change and other global trends. In 2019, the World Health Organization already included dengue in its list
of ten threats to global health.

No antiviral drugs are currently available to prevent or treat
dengue. This may change thanks to the breakthrough discovery of teams
led by Johan Neyts (Rega Institute at KU Leuven) and Patrick Chaltin (CD3/CISTIM Leuven vzw), which was carried forward in partnership with
a team led by Marnix van Loock (Janssen Pharmaceutica, N.V.).

Blocking the 'copier' of the virus The antiviral has a unique
mechanism, explains Professor Johan Neyts of the Rega Institute at KU
Leuven. "Together with the research group of Professor Ralf Bartenschlager
from Heidelberg University, we demonstrated that our inhibitor prevents
the interaction between two viral proteins that are part of a kind of
copier for the genetic material of the virus. If this interaction is
blocked, the virus can no longer copy its genetic material. As a result,
no new virus particles are produced." Together with Professor Xavier de Lamballerie (Aix-Marseille University), the team proved that the antiviral
is very effective against all known variants of the dengue virus.



==========================================================================
The researchers tested the inhibitor in mice as well. Suzanne Kaptein
(Rega Institute at KU Leuven): "Even a low dose of the drug administered
via the oral route proved to be very effective. What is more, the
treatment is still effective when the infection is already at its
peak. In these cases, the number of virus particles in the blood dropped drastically within 24 hours after the start of the treatment. This goes
to show how extremely potent the antiviral drug is." Also suitable for prevention Research in mice suggests that the inhibitor could also be
used for prevention purposes. These findings are cause for optimism,
as the existing dengue vaccine only offers partial protection.

Professor Johan Neyts (KU Leuven): "Potent and safe dengue drugs that
can be easily taken as tablets could offer anyone effective protection
for a certain period of time. Think of people living in areas with an
ongoing dengue outbreak, for instance: they could take a dengue drug
for a couple of days or weeks. The tablets could also protect travellers
or NGO workers during their stay in high-risk regions." The antiviral
drug will be developed in an easy-to-administer formulation that can
be optimised for the treatment and prevention of the disease in dengue-
endemic tropical and subtropical regions.



========================================================================== Twelve-year search The development of the antiviral was a long haul,
says Professor Johan Neyts (KU Leuven). "We started this project in
2009. First, we examined many thousands of molecules in a compound library
of the Centre for Drug Design and Discovery (CD3) to find one or more
molecules that inhibit the virus in lab- grown cells. In other words:
we started looking for a needle in a haystack. As soon as we were able
to identify such molecules, the medicinal chemists at CD3 could start to
work with them. They created many versions of the molecules to boost their efficacy against the virus." There are four types of dengue viruses,
and the molecule needed to be equally effective against all four of them,
adds Patrick Chaltin from the Centre for Drug Design and Discovery. "It
was no easy feat to reach that goal: the optimisation process involved
about 2000 steps. Years of intensive collaboration have now resulted in an ultra-potent dengue inhibitor that we are proud to present." Since 2013, scientists from Janssen Pharmaceutica -- including Marnix Van Loock,
Olivia Goethals, and Tim Jonckers -- have collaborated closely with the KU Leuven teams, accelerating the chemical series into further development.

Ambitions beyond dengue KU Leuven and CD3 have ambitious plans
for the fight against other viruses as well. For one thing,
they are searching for broad-spectrum antiviral drugs against
coronaviruses. Patrick Chaltin: "In the future, we want to develop
a range of antiviral molecules against the different virus families
with pandemic potential, so not just coronaviruses. This will require considerable financial resources, which we are now trying to acquire." ========================================================================== Story Source: Materials provided by KU_Leuven. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Suzanne J. F. Kaptein, Olivia Goethals, Dominik Kiemel, Arnaud
Marchand,
Bart Kesteleyn, Jean-Franc,ois Bonfanti, Dorothe'e Bardiot, Bart
Stoops, Tim H. M. Jonckers, Kai Dallmeier, Peggy Geluykens, Kim
Thys, Marjolein Crabbe, Laurent Chatel-Chaix, Max Mu"nster, Gilles
Querat, Franck Touret, Xavier de Lamballerie, Pierre Raboisson,
Kenny Simmen, Patrick Chaltin, Ralf Bartenschlager, Marnix Van Loock
& Johan Neyts. A pan-serotype dengue virus inhibitor targeting the
NS3-NS4B interaction. Nature, 2021 DOI: 10.1038/s41586-021-03990-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211006112605.htm

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