Metal warheads?

Really out there idea… Can we use a metal as a warhead? Can we look at metal-based drugs in this endeavour? Especially thiophilic metals (Au, Pt, Cu, Pd, etc)? Anyone thought of cisplatin?
Gold complexes are particualrly effective, with track record in HIV, tuiberculosis etc…



Maybe this is a bit out of scope but something we can look at in parallel once we get back?

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Just when you have a good idea, this happens:

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Wow, that is indeed an impressive prediction @JSPEN!

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wort checking it it engages MPro? I’m looking to secure some funds @ Sussex and we could then hopefully finance this and a few other things if successful?

Could we purchase aurofinin and crystallize it in Mpro and show it has activity? This could help in also showing this as a potential mechanism of action and add to the recent paper?

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Auranofin needs host deacetylation to work

I had designed this as a possible replacement for XRC use

https://covid.postera.ai/covid/submissions/ANT-OPE-3ff

One step from cyclohexanethiol and triethylphosphine gold chloride (both able to be purchased from SA)

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FYI: Selenium as a covalent warhead against Mpro https://rdcu.be/b3CNQ

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Let me check with people on this!

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@JSPEN That would be great! Is there any evidence that it would be binding to the protease? Is that how it inhibits HIV?

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Gold works as a sulfur scrubbing warhead @mc-robinson

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@souyakuchan Se might be a bit too unstable - auranofin can be stored under normal atmosphere protected from light - also no Se drugs FDA approved - only Pt and Au

Gold precursor is 74 bucks from sigma - cyclohexanethiol should be available in lab stock

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@stentor @JSPEN @souyakuchan

Just circling back to this since I was reading some repurposing studies tonight.

@stentor could you explain why such activity would have been seen in the study @JSPEN linked without the appropriate host deacetylation. I don’t think i really understand the Mechanism of Action (not sure if anyone truly does on COVID from reading the paper).

And @JSPEN, it looks promising, but I guess we are best suited to do protease assays right now – so my question is if you think we will see anything of use in a protease assay. If Auronafin is indeed acting through the protease then very helpful to confirm that and look into getting a structure – but that whole paper didn’t mention the protease once, so I’m wondering why they don’t suspect that.

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Gold is thiophilic; quite soft so likes SeCys, thiols and thiother residues. I’ve applied for some internal funding; if I get it we can try this and others I hope! I just applied and we should hear soon.

Thrdn reductase:

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To answer your questions, we’d be best to follow stentor’s great advice and look also at the deacetylated complex. My idea would be to test a range of gold complexes.
The paper was a rapid repurposing communication. I guess they wanted to see if the drug had promise vs codid 19 in cells. It’s approved so could be used asap if safe and effective. The MOA would be the least of their worries as they want to cure people or to slow down disease progression, showing it works in cells was a start. We could help the cause by establishing hopefully activity on Cys proteases by auro. and a structural basis. Bioinorganic chemistry is one of my pet projects so it seemed like the right thing for me to propose! Fingers crossed, we can purchase a few analogues and get them tested.
https://pubs.acs.org/doi/full/10.1021/acs.organomet.9b00750

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The auranofin is deacetylated when it enters living cells (the assay that found it as a hit was done in living cells) @mc-robinson

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Do you still have access to your organometallic lab? if so do you have gold precursor and cyclohexanethiol?

To a solution of cyclohexanethiol (0.87 mmol, 102 milligrams) and PEt3AuCl (306 mg, 0.87 mmol) in 1.6 ml of dichloromethane at 0 °C, was added potassium carbonate (145 mg, 1.04 mmol) in reagent grade water (1 mL). The reaction was allowed to warm to room temperature and the stirring continued thereafter for 2h.

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@JSPEN @stentor Great idea! Gold warhead is very interesting. Was just wondering whether this can be done and characterised in a typical med chem CRO, or does this require a special setup?

I’d think enamine could bang out my auranofin analogue no problem - just send them the synthesis I posted and see what they say?

Everything is thought to be air stable: https://doi.org/10.1039/C6GC02908F

@alphalee

It’s trivial chemistry as stentor points out. Our lab is a no go for the mo.
I’m fairly confident we’ll get some funds so hang in there and I hope to have something to pay Enamine to make a few of these (and to cover lab tests and some xray costs) as well as source a few simple gold drugs as in my original post and some simple salts to get a handle on this.
Frank vD and I are on an EPSrC grant so we can also use some of this to contribute but we cannot access our funds @ Sussex at the moment.
Many Unis are looking to freeze expenditure to gain stability in the covid era so a lot of budgets are being frozen.

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Maybe you can extend your algorithms/rxn sequences to include metals such as Au, ferrocene, etc?