Retatrutide (LY-3437943) is an experimental drug for
obesity
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
developed by American pharmaceutical company
Eli Lilly and Company
Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...
. It is a triple
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medic ...
hormone receptor agonist (
GLP-1
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-amino-acid-long peptide hormone deriving from tissue-specific posttranslational processing of the proglucagon peptide. It is produced and secreted by intestinal enteroendocrine L-cells and certai ...
,
GIP, and
GCGR
The glucagon receptor is a 62 kDa protein that is activated by glucagon and is a member of the class B G-protein coupled family of receptors (secretin receptor family), coupled to G alpha i, Gs and to a lesser extent G alpha q. Stimulation of ...
receptors).
It has been shown to achieve a more than 17.5% mean weight reduction in adults without diabetes but with obesity or preobesity (overweight) during a
phase 2 trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
.
[ Free access subject to registration.] In the trial, the participants who received the highest dose (12 mg) showed a mean weight reduction of 24.2% after 48 weeks.
Chemistry
Retatrutide is a peptide with the following amino acid sequence
YA¹QGTFTSDYSIL²LDKK⁴AQA¹AFIEYLLEGGPSSGAPPPS³
where letters with superscripted numbers refer to the following chemical modifications:
# "A¹" refers to
2-aminoisobutyric acid
2-Aminoisobutyric acid (also known as α-aminoisobutyric acid, AIB, α-methylalanine, or 2-methylalanine) is the non-proteinogenic amino acid with the structural formula H2N-C(CH3)2-COOH. It is rare in nature, having been only found in meteorites ...
(Aib).
# "L²" refers to
leucine
Leucine (symbol Leu or L) is an essential amino acid that is used in the biosynthesis of proteins. Leucine is an α-amino acid, meaning it contains an α-amino group (which is in the protonated −NH3+ form under biological conditions), an α-Car ...
modified with an α-methyl substituent (MeL, 2-methylleucine).
# "S³" refers to L-serinamide (L-
serine
Serine
(symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
with the carboxylic acid group replaced with a
carboxamide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent any group, typically organyl groups or hydrogen atoms. The amide group is called a pe ...
).
# "K⁴" refers to L-
lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
with the amino group at position 6 modified with a side chain; specifically, (AEEA)-(γ-
Glu)-(C20 diacid) (where AEEA is 2-
-(2-aminoethoxy)ethoxycetic acid, commonly used as a spacer group in synthetic peptides).
References
GLP-1 receptor agonists
Peptide therapeutics
GIP receptor agonists
Glucagon receptor agonists
Lipopeptides
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