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This was originally published here, in French (link).
We provide this translation for your convenience. Practical aspects may differ where you live.

Islatravir: a remarkable persistence

By Charles-Edouard!

The dilemma of injectables:

In a somewhat rommed vision of the role of historical associations (e.g. Act Up), we see activists struggling with a criticism, sometimes relevant, of therapies. But, for years, none of that! Some declare:
Les ActupienNEs, an association where expertise is our weapon to fight against AIDS in the face of the authorities and the current under-information. (sic)
If you are not funded, you run out of money quickly, and if you are, you shut up! Injectables, as attractive as they are, are a real massacre: overdosing at its peak. And no one, no one to ask the slightest question... That's how it is...

Islatravir and persistence: Stage 3 of development

This ticket is crucial for the future! We must understand the implications... In our previous posts, here and there, we had followed the 'classic' development aiming to gain in efficiency and lose in toxicity. Well... It was funny, but well... An inefficient or toxic molecule would not find a buyer today. So, the gain of efficiency or the loss of toxicity, it's good but it's not likely to move in the houses. With step 3, we're approaching what is so specific to Islatravir, which means that we'll be able to do intermittent treatment more comfortably, but we'll also have to do it: no escape! So, it is important to follow up!

The toxicity of metabolites

The problem of intracellular metabolites: Degradation of nucleobases leads to loss of biological activity of nucleosides and sometimes free nucleobases are toxic. It is therefore desirable that the glycosylated bonds of nucleoside drugs are stable in vivo.

As expected, 4′SdN showed strong activity against all existing resistant HIV strains.

Next, metabolite toxicity was tested in mice. The 2-aminoadenine (EAdA) and guanine (EdG) forms were highly toxic. Degradation by adenosine deaminase is a serious problem in the development of antiviral nucleoside drugs. The researchers finally recognized that 4′SdN (candidate in the previous step) was not a good solution due to its toxicity (metabolites) .

However the 3′-OH group is essential to prevent the emergence of resistant HIV. Different variants have been created: EFdA, EFddA, EFd4A, ECldA... EFddA, EFd4A and Ed4T, d4T, which do not have a 3'-OH group, were effective against wild-type HIV but decreased in activity against resistant HIV. On the other hand, EFdA and ECldA, which have a 3'-OH group, showed excellent anti-HIV activity against wild-type and resistant HIV. In addition, these selectivity indices (the ratio of the toxic dose to the effective dose) were greater than 100,000. This result indicates that one can have both the presence of 3'-OH groups and low toxicity.

It should be kept in mind that in these inhibitors, the original form but especially the tri-phosphate form are active (cf Tenovofir, Abacavir, etc)

EFdA and its triphosphate form, EFdAtriP, are not a substrate of DNA polymerase (no toxicity there...). EFdA is therefore not toxic. The half-life of EFdAtriP in plasma was 17 hours in vitro, but more than 100 hours in vivo, which indicates that EFdAtriP is very stable and remains active in vivo: this indicates that RT also uses the phosphate form, EFdAtriP, as a substrate in vivo. This is the Kiss-Cool effect!

A new mechanism, therefore a new class

The EFdA is now well away from its ancestor, with its sulphurous reputation. We'll see later who this clunky ancestor is and quickly retracted by the marketing teams, who jumped on the observation that EFdA is a translocation-defective RT inhibitor that cannot move from its initial binding position to the next substrate-accepting position because the binding to RT through its 3′-OH and 4′-ethynyl groups is so strong. This is a defective RT inhibitor by translocation. Whew!

(Bah... If you figured that out, hats off!)

No intracellular degradation, in vivo

The trick is there! Once in the cell, Islatravir is metabolized very slowly, the metabolite, itself active, is also metabolyzed very slowly. In a word, it persists ad vitam, so to speak. And who is the good model of an ad vitam persistent inhibitor? Lead (and other heavy metals). If we are not careful, we can reasonably ask ourselves the question of 'lead poisoning' with Islatravir. There would then be a real problem of cumulative dose, which, in the long run, could bring back the toxicities of its infamous ancestor. For the moment, according to the designers, this would not be the case... But it's always the same story!

We will follow with attention how Merck's marketing services could try to hide this, by planting a forest of arguities around this jewel. It started with the idea of selling Islatravir at a dose of 0.75 mg. Now the project is at 20 mg. That suits us... As I said before, I don 't see how Merck will be able to sell this e-th ARV without promoting its only distinctive advantage: persistence!

Weekly intake and 1/15

In fact, the weekly (or even better) oral intake is the objective enemy of the treatment obligation... You may not have realized it, but those who are obsessed with the injection do...

Obligation of treatment / Judiciarization

I guess now everyone understands that the pass, supposedly yours, is in fact remotely disengageable... It's freedom conditioned to the goodwill of whoever runs the central servers. Brrr... We'll have to take refuge in the bush. It's pretty awful, when you think about it.

In the news

- The doctor who made this video is very British... If you can live with it, it is a very clear explanation of the difference between the new Pfizer drug and IVT: New Pfizer drug and ivermectin

- A clarification from D. Raoult on confidentiality in HIV: it concerns us all and it becomes problematic. On this Video, at minute 7:30 We will come back to this, it is really important!

The French genius

This old tune is haunting, we all know it, it comes to us from past times and ballads us: Mon amant de la Saint Jean...

More subtle is this extraordinary film of Jean Cocteau: Le Testament d'Orphée or don't ask me why... You can find the complete version on DailyMotion. It is bizarre, at the limit of understanding, and also very French! very! The Chinese version makes no sense. You can listen again to the magnificent Danse des ombres heureuses (here, Rampal on youtube), extracted from Orpheus. This revolutionary work will trigger a new quarrel after the famous one called "des Bouffons" (which opposed Rameau and Rousseau). Here the partisans of the French operas, the "Gluckists" and those of the Italian opera, the "Piccinists" will clash.

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good weekend, good stuffing and not too many meds ... Huh?