Icotrokinra: Molecular Structure

Molecular Structure#

Icotrokinra (JNJ-77242113, also designated PN-235 and JNJ-2113) is a macrocyclic peptide that represents a significant advance in peptide drug design. Originally discovered by Protagonist Therapeutics and developed in collaboration with Johnson & Johnson, icotrokinra was engineered to achieve oral bioavailability -- a historically difficult challenge for peptide therapeutics.

The molecule is a 13-residue cyclic peptide incorporating both natural and noncanonical amino acids. Its IUPAC name has been disclosed as S3,1,S3,6-cyclo[N-acetyl-3-sulfanyl-L-valyl-L-asparaginyl-L-threonyl-7-methyl-L-tryptophyl-N6-acetyl-L-lysyl-3-sulfanyl-L-valyl-O-(2-aminoethyl)-L-tyrosyl-3-(naphthalen-2-yl)-L-alanyl-4-aminooxan-4-carbonyl-L-alpha-glutamyl-L-asparaginyl-3-(pyridin-3-yl)-L-alanyl-N2-methylglycinamide], indicating the presence of several nonstandard residues designed to optimize binding, stability, and permeability.

Design Principles#

Icotrokinra was designed using constrained peptide engineering approaches to overcome the classical limitations of linear peptides:

1. Macrocyclic backbone: Cyclization via a disulfide bond between modified cysteine residues (referred to as sulfanyl-valine residues) constrains the peptide into its bioactive conformation, reducing the entropic penalty of binding
2. Noncanonical amino acids: Incorporation of residues such as 7-methyl-tryptophan, naphthylalanine, and pyridinylalanine optimizes target engagement and confers protease resistance
3. N-methylation: Reduces the number of exposed hydrogen bond donors, enhancing cell membrane permeability and oral absorption
4. Compact topology: The macrocyclic structure minimizes exposed polar surface area while maintaining the pharmacophore required for IL-23R binding

Chemical Properties#

Pharmacology#

Target Binding#

Icotrokinra binds to the extracellular domain of the IL-23 receptor with picomolar affinity (KD = 7.1 pM at 37 degrees C, as characterized by Fourie et al., Sci Rep 2024). This affinity is comparable to or exceeds that of injectable anti-IL-23 monoclonal antibodies, which is remarkable for a molecule approximately 75-fold smaller than an antibody.

The binding is highly selective for IL-23R over IL-12Rbeta1, the shared subunit between IL-23 and IL-12. This selectivity ensures that icotrokinra blocks IL-23 signaling while preserving IL-12-mediated Th1 immunity, which is important for host defense against intracellular pathogens.

Pharmacodynamics#

By blocking IL-23 from engaging its receptor, icotrokinra prevents:

• Activation of JAK2 and TYK2 signaling
• Phosphorylation of STAT3 (IC50 = 5.6 pM)
• Differentiation and maintenance of pathogenic Th17 cells
• Production of IL-17A, IL-17F, and IL-22 by Th17 and innate lymphoid cells

This cascade reduction in downstream inflammatory mediators underlies the clinical efficacy observed in psoriasis and ulcerative colitis.

Pharmacokinetics#

Icotrokinra was designed for once-daily oral dosing at 200 mg. Key pharmacokinetic features include:

• Oral absorption: The macrocyclic structure with optimized lipophilicity enables intestinal absorption
• Protease resistance: Noncanonical amino acids and N-methylation confer resistance to gastrointestinal and hepatic proteases
• Half-life: Supports once-daily dosing based on pharmacokinetic modeling from Phase 2b data

Stability#

Icotrokinra has been successfully formulated as an oral solid dosage form (tablet), indicating adequate chemical and physical stability for manufacturing, distribution, and storage. The macrocyclic structure provides inherent stability advantages over linear peptides:

• Disulfide cyclization constrains the backbone, reducing susceptibility to enzymatic cleavage
• Noncanonical amino acids are not recognized by most endogenous proteases
• The compact macrocyclic conformation buries peptide bonds, limiting accessibility to degradation enzymes

Structure-Activity Relationships#

The development of icotrokinra reflects decades of advances in macrocyclic peptide chemistry. Key structure-activity relationships include:

• Ring size: The 13-residue macrocycle provides an optimal balance between conformational constraint (for binding) and molecular size (for oral absorption)
• Disulfide vs other cyclization: The disulfide bond provides a reversible constraint that maintains the bioactive conformation
• Noncanonical residues: Each nonstandard amino acid was selected to optimize specific properties (binding affinity, protease stability, or membrane permeability)
• N-methylation pattern: Strategic placement of N-methyl groups reduces polarity without disrupting the binding interface

Related Reading#

• Icotrokinra overview and research guide
• Peptides similar to Icotrokinra
• Icotrokinra research evidence