New active agent against parasites

Date:
October 18, 2021
Source:
Paul Scherrer Institute
Summary:
Researchers have identified a chemical compound that may be
suitable as an active agent against several different unicellular
parasites. Among these are the pathogens that cause malaria and
toxoplasmosis. The point of attack for this promising substance
is the protein tubulin: It helps cells divide and therefore is
essential for the multiplication of the parasites.



FULL STORY ========================================================================== Researchers at the Paul Scherrer Institute PSI have identified a chemical compound that may be suitable as an active agent against several different unicellular parasites. Among these are the pathogens that cause malaria
and toxoplasmosis. The point of attack for this promising substance is
the protein tubulin: It helps cells divide and therefore is essential
for the multiplication of the parasites. The study appears today in the
journal EMBO Molecular Medicine.


==========================================================================
The idea behind this approach comes from tumour research: Blocking
the protein tubulin in cancer cells prevents the cells from dividing successfully -- and thus also from multiplying. Physicians have long been applying this principle successfully in chemotherapy and administering tubulin-inhibiting substances to patients.

PSI researchers Natacha Gaillard and Ashwani Sharma from the Laboratory
of Biomolecular Research have now extended this concept to unicellular parasites, including the pathogens that cause malaria (Plasmodium sp.) and toxoplasmosis (Toxoplasma gondii). Their cells, too, need tubulin for
cell division. "If this protein no longer works the way it is supposed
to, it hits the parasite hard," says researcher Ashwani Sharma. "That
makes tubulin a good point of attack for drugs. The protein has been
known for a long time in tumour research, but until now it hasn't gotten
much attention in parasitology." The pathogens that cause malaria and toxoplasmosis are counted among the apicomplexa, a group of single-celled eukaryotic parasites. Their cells possess a true cell nucleus, and they
go through both sexual and asexual phases of reproduction. Apicomplexa
use humans or animals as hosts or intermediate hosts.

Every year, many millions of people are afflicted by the infectious
diseases they cause.

Searching for points of attack All eukaryotes, from amoebae to humans,
produce the protein tubulin. In the form of long filaments, it spans
the cells as a kind of scaffolding. From this, a so-called spindle
apparatus forms during cell division that pulls the chromosomes apart
and distributes them to two daughter cells.

From one organism to another, the protein differs in just a few places,
but these differences can potentially be important. For scientists to
find active agents against the protein specific to parasites eukaryotic unicellular and thus block it, the precise structure of the protein must
be known.

So PSI researchers isolated tubulin from cells of the ciliate Tetrahymena thermophila. "Its protein is virtually identical to that in apicomplexa," explains scientist Natacha Gaillard. "And that saves us from having
to work with malaria pathogens in the laboratory." Using the Swiss
Light Source SLS and electron microscopy, the researchers deciphered
the molecular structure of the protein. They then searched for a
chemical compound capable of inhibiting the protein. A substance
data bank yielded five candidates as potential active agents -- in the laboratory, one chemical compound proved effective. The researchers named
it parabulin. "It prevents tubulin from forming long, stable protein
filaments. Thus it also blocks successful cell division," Gaillard
says. Parabulin blocks the protein exactly at the place analogous to
where cancer drugs dock in human tubulin.

Hope for future medicine PSI's cooperation partners at the University
of California in Irvine, USA, tested the compound on Toxoplasma gondii
in human cells. And in fact, the parasite was practically incapable of reproducing any more. In contrast, parabulin had virtually no effect on
human cells. "That is a good sign: The substance apparently acts only
on the tubulin of the parasite -- a basic requirement to be able to use
it as a drug against infectious diseases," Sharma explains.

The assumption is that parabulin works not only against Toxoplasma gondii,
but also against all representatives of the apicomplexa, including
the malaria pathogen. PSI has now filed a patent and plans to continue
testing parabulin in the laboratory, with the aim of later developing
it into a drug with the help of the pharmaceutical industry.

========================================================================== Story Source: Materials provided by Paul_Scherrer_Institute. Original
written by Brigitte Osterath. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. N. Gaillard, A. Sharma, I. Abbaali, T. Liu, F. Shilliday,
A.D. Cook, V.

Ehrhard, A.J. Roberts, C.A. Moores, N. Morrissette, M. Steinmetz.

Inhibiting parasite proliferation using a rationally designed
anti- tubulin agent. EMBO Molecular Medicine, 2021 DOI:
10.15252/emmm.202013818 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211018172229.htm

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