KISS1R: Phase 1 Wet-Lab — KP-10 Reference + ncAA Leads C1-01, C1-02

Kiss1r: Phase 1 Wet-lab — Kp-10 Reference + Ncaa Leads C1-01, C1-02

KISS1

Peptide therapeutics — Fertility / Hypogonadism / KISS1R–GPR54 agonism

C1-01 (D-Tyr¹/Arg(Me)⁹) and C1-02 (Ac/D-Tyr¹/Thr⁵/azaGly⁷/Arg(Me)⁹) are ncAA-modified kisspeptin decapeptide agonists of KISS1R (GPR54) selected from the Generation 1 computational pipeline (PRODIGY-estimated Kd 0.64 nM and ~140 pM respectively). This Phase 1 wet-lab compares both leads against the natural-AA reference KP-10 (YNWNSFGLRF-NH2) at Adaptyv (BLI + NPFFR1/NPFFR2 selectivity counter-screens), with cAMP HTRF at Ginkgo on top binders and plasma-stability LC-MS on leads.

Description

Team

PeptAI

Research Lead

Organisation

BIO Protocol

Experiment Cost

$10,000.00

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

TRL 3

TRL 4

Hypothesis formulated

Basic principles observed

Technology concept formulated

Experimental proof of concept

Technology validated in lab

Rationale

The project is entirely computational with no wet-lab experimental work conducted. All evidence consists of molecular modeling, docking simulations, MD simulations, and computational predictions (binding affinity, solubility, immunogenicity). The candidates are explicitly described as 'staged for experimental validation (Gate 9)' with planned experiments at external partners (Adaptyv Bio, Ginkgo Bioworks), but no empirical data has been generated. The presence of a coherent scientific hypothesis supported by clinical validation of the target (MVT-602, TAK-683 precedents) and sophisticated computational pipeline keeps this at TRL 1 rather than Pre-TRL 1.

Assessment

Low Confidence

RecommendationPROMOTE

Total Score4.45

Overall Assessment

This TRL 1 project demonstrates excellent scientific foundation with a score of 4.45/5.0. The therapeutic relevance is exceptionally strong due to validated genetic causation, established mechanism of action in the HPG axis, and clinical precedent from Phase I/II trials of related compounds. The intellectual property position is solid with novel modification combinations, though operating in a field with existing clinical-stage competitors. Therapeutic optionality is moderate, as the mechanism is primarily relevant to reproductive endocrinology. The project represents a scientifically sound concept ready to advance through experimental validation, with well-designed Gate 9 experiments to resolve outstanding computational predictions.

Weighted Score

Project Progress

All updates

All categories

Timeline

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

TRL 3

TRL 4

Hypothesis formulated

Basic principles observed

Technology concept formulated

Experimental proof of concept

Technology validated in lab

Rationale

Assessment

Low Confidence

RecommendationPROMOTE

Total Score4.45

Overall Assessment

Weighted Score

Therapeutic Relevance

The KISS1R mechanism is scientifically robust and clinically validated. Loss-of-function mutations in KISS1/KISS1R directly cause idiopathic hypogonadotropic hypogonadism (IHH), establishing clear genetic causation. Clinical precedents MVT-602 and TAK-683 have advanced through Phase I/II trials demonstrating the target is druggable. The kisspeptin-GnRH-gonadotropin axis is well-characterized, and the mechanism addresses a biologically essential pathway for reproductive function.

Therapeutic Optionality

The mechanism has moderate therapeutic optionality. Primary indication is IHH/fertility disorders, with potential extension to related reproductive endocrine conditions. However, KISS1R's role is relatively specific to the hypothalamic-pituitary-gonadal axis, limiting expansion into unrelated therapeutic areas. The peptide scaffold modifications could potentially be applied to other GPCR targets, but the core concept is focused on reproductive endocrinology.

Intellectual Property

The specific modifications (D-Tyr1, Arg(Me)9, azaGly7 combinations) represent novel compositions of matter with clear patentability potential. While kisspeptin analogues exist (MVT-602, TAK-683), the specific modification patterns and the systematic computational pipeline approach offer differentiation. Prior art exists in the space, but the particular scaffold designs and proteolytic protection strategies appear novel. The 10-compound library provides multiple fallback positions if specific candidates face IP challenges.