Due to popular demand, a thread for the general audience on Molnupiravir, Merck's new treatment for Covid19.

Let's start!
The compound (left) looks like an RNA nucleotide called Cytidine (right) that is found in every cell in nature.

BTW: How do I know it is an RNA nucleotide? You see the two "legs" at the bottom with "OH OH"? If the right leg is OH it is RNA and if it's H, it is DNA. Easy.
The resemblance is nearly perfect except 2 places:
The diff in Blue (isobutylester) is bigger but less important. It's quickly cleaved by an enzyme once the drug is in our body and converted to be identical to a Cytidine.

The "OH" in Red is the magic of this molecule!
There're 4 four type of nucleotides in the body that are the building blocks for RNA/DNA: Adenosine, Cytidine (our guy ⬆️), Guanine & Thymidine*. In short: C,A,G,T.

The colored part 👇 is the base of the nucleotide and confers its identity.

*In RNA, T is a bit different
The four nucleotides attract each other. The Nitrogen-Hydrogen groups (-NH) are more positive and the Oxygen groups (=O) is more negative.
This creates two complementary pairs:
C goes with G
A goes with T

And this is, my friends, how DNA strand can be replicated!!!
Let's take a moment to appreciate this exciting fact that is the basis of every form of life in this planet.
Back to Molnupiravir!
The addition in red creates a new capability. Like a con artist, Molnupiravir looks like a normal C to the viral replication machinery, which incorporates it to its genome.

But the OH addition induces that pairing with an A instead of with a G! Boom!
We just caused the virus to make a mistake in its genetic code. Every time Molnupiravir is incorporated to its genome, it might put an A instead of G. When there are many mistakes, it cant no longer read its replication machinery and becomes a useless piece of RNA.
BTW, many antivirals utilize a similar concept: give a faulty nucleotide to a replicating virus so it will destroy itself in the process. For instance, Remdesivir is a nucleotide that mimics an A, but is supposed to halt the replication machinery instead of mutating the genome.
Look how nicely Molnupiravir inhibits SARS-CoV-2 in a cell line. The x-axis shows growing concentrations of the drug and the y-axis shows the reduction in viral load (up = less virus). Once we rich a critical concentration, all viruses are dead 😍.
Source: science.org/doi/full/10.11…
Interm summary: Molnupiravir is a drug made of RNA. Unlike the vaccines, it isn't a long molecule that encodes a protein. It's just a single nucleotide that acts as a trojan.
Also the doses are different:
Pfizer vax is 0.00003gr/dose
Here is 0.8gr/dose!
Why do we need this super-sized dose???
We want that in every target cell (e.g. lung), we will have enough of this nucleotide, so a replicating virus will incorporate it with high probability and commit a suicide.
This brings us to talk about the safety of Molnupiravir.

One worry is that the human cell will also incorporate this nucleotide to their genome, creating mutations. Indeed, this is an RNA nucleotide but there are enzymes that can convert it to a DNA form.
1 At least one manuscript reported that cell cultures can mutated due to this drug.
2 The former head of @BARDA, @RickABright also expressed concerns in his whistleblower letter.
3 Merck excluded pregnant women from their trial.

But is the drug unsafe?
Not essentially. It might be that a short exposure is totally OK. However, it will be interesting to see the safety data that @Merck presents to the @US_FDA and how they excluded any long term risks, especially for relatively young patients.
The second worry is the induction of new viral strains. Essentially, we are increasing the mutation rate of the virus! Is it a problem?
I am less worried about this one. Viruses optimized their mutation rate. Too slow=static target. Too fast=destroying themselves.
However, I would love to see the sequencing results of viruses from a patient with partial compliance (for instance someone who took only one pill out of the ten recommended ones). Again, let's wait for more data.
Final thought: some people asked me whether Molnupiravir is similar to Ivermectin. The answer is NOT AT ALL. Ivermectin is not a nucleotide and is not incorporated to viral genome. It works against parasites by going after an ion channels that viruses don't have.
Molnupiravir is a good step forward but not a magic. The results are nice but it will be interesting to see the FDA decision including the safety profile.

And between this or a vaccine, I will definitely go with the vaccine.

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More from @erlichya

2 Oct
שרשור על מה זה Molnupiravir, התרופה החדשה של Merck כנגד Covid19.
יאללה מתחילים.
הדבר הראשון שרואים היא שהתרופה (משמאל) נראית כמו נוקלאוטיד RNA שנקרא Cytidine ומצוי בכל תא של אורגניזם בטבע (מימין).

אגב, איך אני יודע שזה נוקלאוטידים של RNA ולא DNA? רואים למטה כמו שני רגלים עם OH בכל צד? אז אם הרגל הימנית היא OH, זה RNA, ואם היא פשוט H, אז זה DNA. קל!
הדימיון כמעט מושלם חוץ משני מקומות:
השינוי בכחול הוא לא כזה חשוב לענייננו. מדובר בתוספת שיורדת מהר מאד בגוף על ידי אנזים מיוחד ומחזיר אותנו למצב כמו ב Cytidine רגיל.

השינוי ה OH בחלק שסימנתי באדום הוא הקסם של המולקולה הזאת שהופכת אותה מסתם Cytidine לסוכן כאוס.
Read 17 tweets
27 Sep
covid19 in 🇮🇱.

Due to ✡️ holiday season, it is hard to get a reliable estimator of R. Previously, I showed that the avg susceptiblity of ISR population (S) is nicely correlated with R. This estimator is not affected by # test but only by # vaxxed and VE.
As a reminder, S(t), the susceptiblity of day t is 1 - Σf_i(t) •VE_i(t). Where f_i(t) is the % of the population that already took the i-th dose and VE is the efficacy of the dose in day t. Both parameters can be in calculated from MoH public dashboard on a daily basis.
So here is S as a func of time (black) versus smoothed R (red). Both are coorelated.

Now, we don't have good data for R in Sep, BUT due to booster, S is in levels similar to Mar 21 (60%)! At that time, it was enough for R=0.9, so I'm cautionally encouraged that we= heading out😍
Read 4 tweets
27 Sep
לפני כשבועיים הצגתי את מדד ה susceptibles.

המדד (קו שחור) משערך את % האנשים שחשופים להדבקה וצופה לא רע של R (קו אדום). אבל בניגוד ל R, הוא לא תלוי בכמות הבדיקות אלא רק ב% המחוסנים ויעילות כל מנה (מדד נמוך=טוב יותר).

אז המדד (קו שחור) היום באותה רמה של 3/21, כלומר צופה R<1😍 Image
עוד פרטים: המדד אומר שאם לוקחים את אחוזי המתחסנים בכל מנה ואת היעילות של המנות בכמה ימים האחרונים, יש באוכלוסיה פחות מ 60% אחוז אנשים שחשופים להדבקה. במרץ, עם ההגבלות, זה הספיק. היום יש דלתא מצד אבל עוד 300 אלף מחלימים. בזהירות: נראה שאנו מעבר לשיא, כל זמן שיעילות החיסונים תמשיך.
עוד משהו מעניין בעבודה על המדד הוא יעילות מנה 2 נגד תחלואה. שמו לב לשיפור באוג׳. השיפור נובע ככה״נ שמי שהתחסן במנה 3, היו בדיוק אלה שהיו הכי זקוקים לכך: מבוגרים עם מנה 2 ביעילות אפסית. ברגע שהם יצאו מהמדגם, נשארנו עם צעירים ביעילות משופרת (אבל עדיין רחוקה מלהיות טובה כמו בהתחלה). Image
Read 4 tweets
16 Sep
Israel 🇮🇱, booster 💉💉💉, and herd immunity 🐑.
A thread based on the Ministry of Health data with many graphs.
Let's dive!
Many of you heard about the decline of vaccine effectiveness in Israel in the past few months. The MoH publishes now on a daily basis the rate of infection in unvaxxed, vaxxed (2nd dose), and boosted individuals per 100K, which is a real treasure!
With this data, we can determine the **crude** VE of each group by dividing the rate of infection in second dosed individuals to unvaxxed. From Jan 2020 to now, this is the crude VE (crude = not adjusted to sex, age, and other demographic variables)
👇👇👇 Image
Read 10 tweets
15 Sep
שרשור על חסינות האוכלוסיה בישראל והתפשטות התחלואה. איפה היינו ולאן אנחנו הולכים.
יהיה גרפים 📊. ויהיה מעניין!
עם הדאטה בדאשבורד אפשר עכשיו לחשב בכל יום החל מינואר את יעילות הגולמית של מנה 2 לעומת לא מחוסנים. מה אנחנו רואים כאן בעצם? זה פשוט יחס המאומתים בין מחוסנים 2 ללא מחוסנים בכל יום לאחר נירומול לגודל האוכלוסיה. זאת יעילות גולמית כי היא לא מתקוננת למגזר או גיל (אבל לאחר החלקה).
שימו לב לעליה הקטנה ביעילות באזור תחילת מרץ. אני מניח שזה נגרם כתוצאה מהתחסנות האוכלוסיה היותר צעירה בסוף ינואר, ששם החיסון יעיל יותר מאשר באוכלוסיה המבוגרת.
סביב החצי הראשון של חודש אפריל הקסום, למתחסן הממוצע היה יעילות גבוהה מאד. ואז החלה השחיקה שהביאה לנפילה חופשית במאי-יוני.
Read 10 tweets
7 Sep
Important data from Israel: the relative protection against contracting Covid19 at the 4th wave as a function of vax/prior reinfection status. The data is calibrated to RR=1 for people who received 2nd dose in Jan and no booster.

A few thoughts below on waning protection👇
One important take away is that a prior infection protects you but can wane without a vax. People who contracted covid during the 2nd wave (Sep-Oct 20; dark red) have 1.9x risk to get delta compared to people who contracted Covid during the 3d wave (Jan-Feb 21; light red).
Recall that Alpha (3rd wave) is not closer to Delta (4th wave) than the ancestral strain (2nd wave). So it is reasonable to assume that diff are due to waning immunity.

This means that a recovered person looses ~15% of the protection per month. After 2yrs =~ no protection.
Read 7 tweets

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