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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.

Genesis of Islatravir: 1- Race for Efficiency

By Charles-Edouard!

Islatravir and Soy Sauce

To understand Islatravir and what I'm going to talk about today, you have to be sure you've read this first post, because Islatravir is a novel that starts a thousand miles away from 1/15...

At the beginning was a group of Japanese university researchers who were looking for ways to add value to food products, by breaking molecules to make 'valuable' molecules at lower cost... In a word, cutting a big molecule, existing and cheap, rather than synthesizing, ex-nihilo. Vast program where the Ministry married them with a local Kronenbourg, a brewer of beer (agrobusiness, we say...).

The idea is to cut 'natural' molecules into elementary bricks. This allows to manufacture animated acids for which the market (pharmacy, biology,...) is emerging. The beer brewer doesn't care about this, but a manufacturer of Soy sauce, the one that decorates your Sushis (yes, yes...) has a division of specialized products. Yamasa (Soy Sauce) takes the place of Asahi (Beer) in this academic project. Surprising, isn't it? Neither Merck nor the usual parrots will tell you this. Because Merck will defend itself from the shameless price it will get for its research efforts, which were insignificant, as we shall see...

Islatravir and Efficacy Gain

The project is the manufacturing by (enzymatic?) cutting of molecules in bricks, with very high added value, at lower cost... At the turn of the century, the most expensive molecules, facing huge challenges of industrialization, are the ARVs, which the (third) world needs so much. So here are our brilliant university chemists(paid by the penny) who undertake to make a derivative ARV, which costs less! Thus saving the world from a certain AIDS death.

A major track is the increase of efficiency. Indeed, if we use less drugs for the same effect, it costs less per patient. Leibowitch develops a method(largely ignored by the medical-pharmaceutical mafia) which divides the cost by 10. The Japanese chemists will reduce the cost by ... One thousand!(and we will combine the two, hi, hi, hi... ). Efavirenz is 600 mg, Islatravir is 0,75 mg, which makes a ratio of 1 to 1000, by a ladleful!

So here are our chemists who start with an expensive molecule and try to improve it. Well... The scheme is hyperclassic, we start from a molecule with a known but moderate efficiency and we try to adapt the molecule to its target. A vast program!

Step 1: better resistance profile but high toxicity...

NRTIs are 2', 3'-dideoxynunucleoside (ddN) derivatives whose efficacy is due to the fact that nucleosides are RT chain terminators (CT). However, all these drugs have a low barrier to resistance. Since the structural difference between dN and ddN is whether or not they have 3'-OH, they surmised that the presence or absence of 3'-OH changes the resistance profile. A 4'-substituted 2-desoxynucleoside (4'SdN) substituent at the 4'-position was designed to achieve this goal (Fig. below).

In their hypothesis, the new compound can be recognized by Reverse Transcriptase (of HIV), and mess with it... That would be cool! The problem is that it is also recognized by the human DNA polymerase, which would be highly toxic.

Step 2: solve the toxicity problem...

Well yes... We might be able to treat better, of course, but increasing toxicity is not great, especially in the context of the 2000s. We will see next time how they solved this problem

Obligation of treatment / Judiciarization

The idea of making screening compulsory, regular, for all, from 15 to 75 years old, for transmissible diseases (HIV, HCV, Syphillis, etc) seems to me to be quite acceptable: screening is without danger, by itself it allows to reduce the epidemic, it does not imply a compulsory treatment. Voluntary screening with community pressure on risk groups has had its day: it is useful but we have reached a plateau. While we have spent crazy amounts of money(yours) for a virus that probably escaped from a research center(not from our country), we could finally put in place a total strategy of multiple screening. Of course, the associations, who gain from the 'targeting' and the martyrdom of the afficinados of natural contraceptive penetration, are against it. What the hell!

They are against you as patients and participate in the expansion of the epidemic, under the guise of fighting against it. They are the objective ally of BigPharma, which would not be at all happy with the extinction of the epidemic. Have we ever seen these associations of frightened seronegs come to your rescue for the intermittence? Never... Total radio silence.

Protocol medicine is becoming totalitarian medicine... It is inevitable!

In the news

- The front line in the global war on Benevolent Medicine is currently in the state of Goa, India. Maudrux, bothered by the Council to the Orders, is following up on it, here. This state has taken it upon itself to deal with the Indian resurgence of the epidemic by distributing Ivermectin widely. The crisis is being contained, which no one is talking about. After Chiapas, all of Mexico is getting in on the act. Opposite Goa, Tamir Nadul (180 million inhabitants) is a comparison for having followed the negative advice of the WHO and thus backed off. Two regions, in the same area, epidemic at the same time, 2 opposite strategies, this makes a credible judge of peace. Concerned' but not destitute doctors have taken the case against the State of Goa to the Supreme Court, citing the negative warning of the WHO. The Government of Goa, defends its initiative, with arguments in support. The Supreme Court lets it go ahead: see here...(one will remember the role of an Indian Supreme Court in the resolution of the Gordian knot where the ARV industry had taken the HIV world hostage)

- Remarkable interview with Prof. Montagnier: we will come back to it, one day, because his argument on the thermodynamic stability of DNA deserves our attention. The argument has its part in my strategy of reducing the reservoir.

- The IHU (Pr Raoult) publishes its series of 10,000 patients treated in day hospitals: no deaths in patients under 60 years of age, if HCQ/AT. If we exclude very old patients with low life expectancy (heavy comorbidities), they have only 3 deaths out of 10,000, if HCQ/AT. This is the largest single-center series in the world! Greetings to the Pharisees!

The French genius... seen from America...

Did you know that? The late Anthony Perkins (Hitchcock's Psycho), sadly deceased from AIDS, had tried his hand at French song. There is no more after in Saint-Germain... It's nice, and touching. You Tube offers it to you. Let's enjoy it !

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