<Long Story short: Rationale for the broad spectrum antiviral activity of Niclosamide: it’s a biophysical proton “shuttler” … no biological target required>
Hi Twivoids – I am a Virologist by training and used to be an avid follower of TWIV for many years – a switch in careers let me lose touch with the field for a while but Covid drove me back to following TWIV.
I wanted to comment on TWIV 742: I did my PhD on host-factor targeted antivirals with Urs Greber at the Uni Zurich. We identified Niclosamide as a broad-range antiviral back in the days – long story short, we found that Niclosamide is a “biophysical” protonophore. A phenotypic infection screen of approved compounds led to the initial Hit – plenty of cell biology, medicinal chemistry and biochemistry later we concluded that Niclo doesn’t require a biological target (shown in vitro with liposome assays etc.); in simple terms: the lopP (partition coefficient between H20 and the hydrophobic phase) of Niclosamide switches in a pH dependent manner – Niclo becomes more hydrophilic in an acidic environment => it diffuses through membranes and preferentially carries out the proton of e.g. endosomes; notably this mode of action does not require any biological target at all – but one will see a lot of biological downstream effects (as in e.g. proton-gradient driven ion gradients and mechanisms controlled by these etc.). It seems like that Niclo has just the right properties to affect many pathways which are required for viral infections but just enough not to affect the host too much.
The IC50’s reported in various models well support this mode of action to be the key driver of efficacy.
After having worked in biotech and drug development for more than a decade I am still fascinated by the pure physicochemical mechanism explaining the Niclo effect – lots of implications e.g. we never managed to produce escape mutants.
As a biologist one intrinsically is biased to look for biological targets hence I believe the Niclo story is so relevant since it bridges classical cell biology with biophysics.
All the best & thanks a lot for all the great work you are doing – TWIV is my trusted source on virology and I recommend it to many of my friends and colleagues! A paper often only reaches a few people but TWIV serves as a catalyst, bridging the world of data driven-science with the more complex world we are all living in.
PS.: I hate citing myself but maybe relevant to ref the original paper
Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects
Andreas Jurgeit,Robert McDowell,Stefan Moese,Eric Meldrum,Reto Schwendener,Urs F. Greber
Published: October 25, 2012https://doi.org/10.1371/journal.ppat.1002976
Andreas Jurgeit, PhD
I figured this may be of interest to you. Thanks as always for providing great info!
A comparison of vaccine efficacy (though they conflate efficacy with effectiveness in the title) using absolute risk reduction instead of relative risk reduction:
SoCal aerospace engineer and 14 month TWiV listener. You know what the weather is here 😉
Hello TWIV team,
Firstly, thank you for taking the time to put out such a helpful and useful podcast, not only for SARS-CoV-2 but for other aspects of virology as well! It’s been a great resource of information for me as a new graduate student who doesn’t have much of a background in virology.
I’m emailing from Northern Indiana (where there has been snow today, in late April) after listening to TWIV 743 on shape-shifting viruses. I really appreciated the discussion of viral particle shape, and the possibility of spherical viruses potentially being an artifact of culture was also a learning moment for me. Going off of that, I wanted to ask if this has implications for what we currently know about IAV or other viruses? Particularly in terms of infectivity, neutralization, or vaccine and therapy development?
It is currently 29C/85F, drizzling and 70% humidity in Bangkok. The number of reported cases has been rising to about 1000-1500 per day the past month, and a total of 45000 reported cases and 108 deaths out of a population of 70 million since the beginning of the pandemic.
There is a policy requiring anyone who tests positive (by RT-PCR) to enter a hospital for 14 days, even if the person has no symptoms. Most of the hospital beds are not in isolation wards and new field hospitals such as the one shown in the photo put large numbers of SARS2 positive-tested persons together.
My question is whether this practice constitutes an unnecessary risk for creating potentially dangerous variants? The case mortality ratio is very low, so it seems to me the best thing would be to hospitalize only those patients who are at high risk. In my view they should be using rapid antigen tests rather than RT-PCR for screening.
How do you see this? Vaccines are not yet widely available.
Thanks for your ongoing work to educate the world about virology.
All the best
Rita Anne writes:
Hello Daniel,Brianne,Kathy,Amy,Alan,Rich,Dickson,and Vincent,
My equanimity is upset every time you say there is no need for the Janssen vaccine since everyone can get mRNA vaccines. This is not true now for many people in rural areas, for homebound people, and definitely not for many poorer countries.
I am surprised by this since you usually do consider conditions in the rest of the globe.
We are two retired on Cape Cod and the Cape had a lot of trouble getting the vaccines here. Although we have the oldest population, Barnstable county was getting dribs and drabs. Once Janssen became available it became possible to have enough vaccination clinics so we oldsters could get vaccinated (we were very pleased to get Janssen). With the suspension of Janssen (why not a warning and let people decide with advice from physicians?) several of the clinics have been cancelled.
This is a consequence of the suspension you do not seem to be considering.
Just saw/heard Gorilla episode- really interesting.
Rita and Les Garrick
Retired PhDs in Physiology and Physiological Zoology from
Woods Hole where it is actually sunny and warm 50’s for us.
Addicted to TWIV but you are out of TWIV hats!!
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