Sunday, 9 August 2020

How not to repurpose a 'drug'

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I sometimes wonder what percentage of the pharmacopoeia will have been proposed for repurposing for the treatment of COVID19 by the end of 2020. In particular, I worry about the long-term, psychological effects on bloggers such as Derek who is forced to play whack-a-mole with hydroxychloroquine repurposing studies. Those attempting to use text mining and machine learning to prioritize drugs for repurposing should take note of the views expressed in this tweet

The idea behind drug repurposing is very simple. If an existing drug looks like it might show therapeutic benefits in the disease that you’re trying to treat then you can go directly to assessing efficacy in humans without having to do any of those irksome Phase I studies. However, you need to be aware that the approval of a drug always places restrictions on the dose that you can use and route of administration (for example, you can't administer a drug intravenously if it has only been approved for oral adminstration). One rationale for drug repurposing is that the target(s) for the drug may also have a role in the disease that you’re trying to treat. Even if the target is not directly relevant to the disease, the drug may engage a related target that is relevant with sufficient potency to have a therapeutically exploitable effect. While these rationales are clear, I do get the impression that some who use text-mining and machine learning to prioritize drugs for repurposing may simply be expecting the selected drugs to overwhelm targets with druglikeness. 

There are three general approaches to directly tackle a virus such as SARS-CoV-2 with a small molecule drug (or chemical agent). First, destroy the virus before it even sees a host cell and this is the objective of hand-washing and disinfection of surfaces. Second, prevent the virus from infecting host cells, for example, by blocking the interaction between the spike protein and ACE2. Third, prevent the virus from functioning in infected cells, for example, by inhibiting the SARS-CoV-2 main protease. One can also try to mitigate the effects of viral infection, for example, by using anti-inflammatory drugs to counter cytokine storm although I’d not regard this as tackling the virus directly.

In this post, I’ll be reviewing an article which suggests that quaternary ammonium compounds could be repurposed for treatment of COVID-19. The study received NIH funding and this may be of interest to researchers who failed to secure NIH funding. The article was received on 06-May-2020, accepted on 18-May-2020 and published on 25-May-2020. One of the authors of the article is a member of the editorial advisory board of the journal. As of 08-Aug-2020, two of the authors are described as cheminformatics experts in their Wikipedia biographies and one is also described as an expert in computational toxicology. 

The authors state: “This analysis identified ammonium chloride, which is commonly used as a treatment option for severe cases of metabolicalkalosis, as a drug of interest. Ammonium chloride is a quaternary ammonium compound that is known to also have antiviral activity (13,14) against coronavirus (Supplementary Material) and has a mechanism of action such as raising the endocytic and lysosomal pH, which it shares with chloroquine (15). Review of the text-mined literature also indicated a high-frequency of quaternary ammonium disinfectants as treatments for many viruses (Supplementary Material) (16,17), including coronaviruses: these act by deactivating the protective lipid coating that enveloped viruses like SARS-CoV-2 rely on.” 

Had I described ammonium chloride as a “quaternary ammonium compound” at high school in Trinidad (I was taught by the Holy Ghost Fathers), I’d have received a correctional package of licks and penance. For cheminformatics ‘experts’ to make such an error should remind us that each and every expert has an applicability domain and a shelf life. However, the errors are not confined to nomenclature since the cationic nitrogen atoms of a quaternary ammonium compound and a protonated amine are very different beasts. While a protonated amine can deprotonate in order to cross a lipid bilayer, the positive charge of a quaternary ammonium compound can be described as ‘permanent’ and this has profound consequences for its physicochemical behavior. First, the protonation state of a quaternary ammonium nitrogen does not change in response to a change in pH. This means that, unlike amines, quaternary ammonium compounds are not drawn into lysosomes and other acidic compartments. Second, the positive charge needs to be balanced by an anion (in some cases, this may be in the same covalent framework as the quaternary ammonium nitrogen). Despite being positively charged, the quaternary ammonium group is not as polar as you might think because it can’t donate hydrogen bonds to water. However, to get out of water it needs to take its counterion (which is typically polar) with it. I like to think about quaternary ammonium compounds (and other permanent cations) as hydrophobic blobs that are held in solution by the solvation of their counterions. A typical quaternary ammonium compound can also be considered as a detergent in which the polar and non-polar parts are not covalently bonded to each other. 

My view is that the antiviral ‘activity’ reported for ammonium chloride and chloroquine is a red herring when considering potential antiviral activity of quaternary ammonium compounds because neither has a quaternary ammonium center in its molecular structure. Nevertheless, I consider “raising the endocytic and lysosomal pH” to be an unconvincing ‘explanation’ for the antiviral ‘activity’ of ammonium chloride and chloroquine since one would anticipate analogous effects for any base of comparable pKa. One should also anticipate considerable collateral damage to result from raising the endocytic and lysosomal pH (assuming that the ‘drug’ is able overwhelm the buffering systems that have evolved to maintain physiological pH in live humans). The pH raising ‘explanation’ for antiviral ‘activity’ reminded me of suggestions that cancer can be cured by drinking aqueous sodium bicarbonate and I’ll direct readers to this relevant post by Derek. 

This brings us to cetylpyridinium chloride and miramistin shown below and I’ve included the structure of paraquat in the graphic. While miramistin does indeed have a quaternary ammonium nitrogen in its molecular structure, cetylpyridinium chloride is not a quaternary ammonium compound (the cationic nitrogen is only connected to three atoms) and would be more correctly referred to as an N-alkylpyridinium compound (or salt). Nevertheless, this is a less serious error than describing ammonium chloride as a quaternary ammonium compound because cetylpyridinium is, at least, a permanent cation. Neither cetylpyridinium chloride nor miramistin are quite as clean as the authors might have you believe (take a look at L1991 | L1996 | D2017 | K2020 | P2020). I’d expect an N-alkylpyridinium cation to be more electrophilic than a tetraalkylammonium cation and paraquat, with two N-alkylpyridinium substructures is highly toxic. Would Lady Bracknell's toxicity assessment have been that one N-alkylpyridinium may be regarded as a misfortune while two looks like carelessness?
I have no problem with hypothesizing that a chemical agent, such as cetypyridinium chloride, which destroys SARS-CoV-2 on surfaces could do the same thing safely when sprayed up your nose, into your mouth or down your throat. If tackling the virus in this manner, you do need to be thinking about the effects of the chemical agent on the mucus (which is believed to protect against viral infection). The authors assert that cetylpyridinium chloride “has been used in multiple clinical trials” although they only cite this study in which it was used in conjunction with glycerin and xanthan gum (claimed by the authors of the clinical study to “form a barrier on the host mucosa, thus preventing viral contact and invasion”).

The main challenge to a proposal that cetylpyridinium chloride be repurposed for treatment of COVID-19 is that the compound does not appear to have actually been conventionally approved (i.e. shown to be efficacious and safe) as a drug for dosing as a nasal spray, mouth wash or gargle. Another difficulty is that cetylpyridinium chloride does not appear to have a specific molecular target. Something that should worry readers of the article is that the authors make no reference to literature in which potential toxicity of cetylpyridinium chloride and quaternary ammonium compounds is discussed.

This is a good place to wrap up and, here in Trinidad's Maraval Valley, I'm working a cure for COVID-19. I anticipate a phone call from Stockholm later in the year.

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