pe
pep-05144 v1 CC-BY-SA-4.0

Calcitonin metabolic peptide

An experimental peptide aimed at the same body system targeted by modern weight and blood-sugar drugs, still in research, not an approved medicine.

statuscomputed targetGLP-1R length32 aa refs1
metabolic
EARLY ENTRY This candidate is newly indexed — supporting evidence is still being added. Have a paper or data point? Contribute below.
status 2 / 5 · 2 contributors
prediction metrics boltz-2 1.0
ipTM0.728
pTM0.817
avg pLDDT70.3
ranking score0.708
STRUCTURE · PEP-05144 × GLP-1R
ranking0.708
target interface 4.5Å peptide drag rotate · ctrl+scroll zoom · right-click pan
boltz-2 1.0 · mmCIF ↓ download
sequence32 aa
15101520253032
CGNLSTCMLGTYTQDL NKFHTFPQTSIGVGAP
in the news 136 articles
Hypotheses7 directions▾ collapse

Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.

openupdated 2026-06-05

Can two targeted tweaks fix the chemical fragility of this molecule before anyone spends money testing it?

If these modifications hold up in the lab, researchers would have a stable, potent starting point for a new class of weight and bone drugs, cutting the time and cost of early development. This matters most to labs deciding whether to invest in making and testing the molecule.

The hypothesis
Introducing a C-terminal amide (Pro-NH2) at position 32 of pep-05144 and replacing M8 with norleucine to prevent methionine oxidation would yield an analog with improved chemical stability and enhanced CTR potency, converting this computed peptide into a synthesis-ready lead.
Why it’s plausible
Two known liability points in this sequence are: (1) the free C-terminal carboxylate at P32, which in calcitonin family peptides reduces CTR binding affinity relative to the amidated form; and (2) M8 (methionine at position 8), which is susceptible to oxidation during synthesis and storage, a known problem for calcitonin itself. Norleucine is isosteric with methionine but not oxidizable and is used in calcitonin analogs (sCT analogs). The manufacturing axis hit (10.1038/nrd1331) notes that calcitonin-class peptides are manufactured synthetically at scale, establishing that a 32-residue peptide with these modifications is within SPPS feasibility. Together these two modifications address the primary chemical stability and potency gaps without altering the pharmacophore.
Why it matters
Demonstrating that two minimal modifications (C-terminal amide and Nle8 substitution) recover potency and stability would validate the scaffold as an engineerable template, de-risking the investment in bioassay development and establishing pep-05144 as a starting point for a calcitonin-family metabolic peptide program.
Plausibility.75
Novelty.32
Impact.62
Basis · grounding1 paper · 3 computed/notes
[1]
sequenceM at position 8 is the only methionine; susceptible to oxidation; norleucine substitution is established practice in calcitonin analogs
[2]
sequenceP at position 32 is the C-terminal residue without amidation; adding Pro-NH2 mimics native calcitonin C-terminus known to enhance CTR affinity
[3]
sourceManufacturing axis hit confirms calcitonin-class peptides are routinely produced by SPPS, establishing synthetic feasibility for a 32-mer with these modifications
[4]
paper
IUPHAR review documents C-terminal amidation as a pharmacophore feature across calcitonin family members at CTR
doi: 10.1111/bph.14075
openupdated 2026-06-05

Could the shape of this peptide be tuned so it triggers the bone-protecting signal without causing the body to quickly stop responding?

Long-term calcitonin therapy loses effectiveness because the body adapts and internalizes the receptor. If this peptide could be designed to favour the bone-protecting signal over the adaptation signal, it might offer more durable treatment for osteoporosis or metabolic conditions. That would matter for patients who currently see calcitonin stop working over time.

The hypothesis
The N-terminal disulfide ring of pep-05144 (C1-C7) adopts a type II beta-turn conformation that is necessary and sufficient for receptor engagement, while the central helix-forming region (residues 10-22) determines signaling bias between cAMP and beta-arrestin pathways at CTR.
Why it’s plausible
X-ray crystallography of salmon calcitonin bound to CTR (Johansson et al. 2016, referenced in the lit chunk) revealed that the bound peptide adopts a type II turn in the ring region and an alpha-helix in the central segment. Calcitonin family peptides show biased agonism at CTR: cAMP pathway activation versus beta-arrestin recruitment can be differentially tuned by the central helix. In pep-05144, residues MLGTYTQDLNK (positions 8-18) have the amphipathic character expected of a helix that docks into the transmembrane bundle, but with distinct hydrophilic face residues (Q, D, N) compared to sCT. This altered hydrophilic face could shift the relative efficacy for Gs-cAMP signaling versus beta-arrestin-mediated internalization.
Why it matters
Signaling bias at CTR is physiologically important because cAMP-driven pathways mediate bone resorption inhibition while beta-arrestin recruitment drives receptor downregulation and tachyphylaxis. A peptide biased toward cAMP over internalization would have more durable bone and metabolic effects, addressing the tachyphylaxis that limits long-term calcitonin use.
Plausibility.57
Novelty.45
Impact.58
Basis · grounding2 papers · 1 computed/note
[1]
paper
Johansson et al. 2016 crystal structure of receptor-bound salmon calcitonin, showing type II turn at N-terminal ring
doi: 10.1111/bph.14075
[2]
sequenceResidues 8-18 MLGTYTQDLNK have amphipathic character compatible with helix formation, but hydrophilic face differs from sCT at positions Q13, D14, N16
[3]
paper
JBC paper on peptide-binding modes and allosteric modulation of calcitonin receptor by RAMPs, relevant to signaling pathway coupling
doi: 10.1074/jbc.m115.713628
openupdated 2026-06-05

Is this peptide specific enough that it won't accidentally activate receptors that control blood vessels in the head?

Drugs that unintentionally hit the CGRP receptor can cause vascular side effects. If this peptide's structure naturally avoids that receptor, as this hypothesis suggests, it could have a cleaner safety profile for people using it long-term for weight or metabolic management.

The hypothesis
Pep-05144 shows lower potency at the CGRP receptor (CLR/RAMP1) than at CTR-based AMY receptors because its ring size (C1-C7, 7-residue ring) matches the calcitonin scaffold rather than the CGRP scaffold (C2-C7, 6-residue ring), and CLR selectivity requires the shorter ring and specific CLR-contacting residues absent in this sequence.
Why it’s plausible
The calcitonin/CGRP family receptor selectivity is heavily determined by the N-terminal ring size and sequence. CGRP has a 6-residue ring (C2-C7) and binds CLR/RAMP1 but not CTR. Calcitonin has a 7-residue ring (C1-C7 equivalent) and binds CTR but not CLR. Pep-05144 has C at positions 1 and 7, giving a 7-residue ring topology if the disulfide forms, which is a calcitonin-class ring. The selectivity axis hits in the evidence bundle (10.1111/j.1476-5381.2011.01525.x) specifically discuss CLR residues important for CGRP high-affinity binding and document that calcitonin does not bind the CGRP receptor with meaningful potency.
Why it matters
Confirming CGRP receptor non-engagement is important for safety: CGRP receptor antagonism is the mechanism of anti-migraine gepants, and unintended CGRP receptor engagement by a metabolic peptide could cause unwanted vascular effects. Conversely, low CGRP receptor activity would support a cleaner metabolic safety profile.
Plausibility.65
Novelty.20
Impact.48
Basis · grounding2 papers · 1 computed/note
[1]
sequenceC1 and C7 define a 7-residue N-terminal ring, consistent with the calcitonin scaffold (7-residue ring) rather than the CGRP scaffold (6-residue ring)
[2]
paper
Selectivity axis hit identifies CLR residues critical for CGRP high-affinity binding, which would be absent in the CTR-based receptor context
doi: 10.1111/j.1476-5381.2011.01525.x
[3]
paper
IUPHAR review pharmacology figure shows CGRP receptor (CLR/RAMP1) versus AM receptors (CLR/RAMP2 and CLR/RAMP3) with distinct agonist profiles
doi: 10.1111/bph.14075
openupdated 2026-06-05

Could this molecule reduce hunger and improve blood sugar through the same mechanism as the approved drug pramlintide, but with a different structure?

Pramlintide works but has practical drawbacks, including injection-site reactions. If this peptide hits the same receptor through a structurally distinct sequence, it could open a path to improved formulations, or even a dual-action drug that pairs well with GLP-1 therapies like semaglutide. This would be relevant to people managing obesity or type 2 diabetes.

The hypothesis
Pep-05144 activates the AMY1 receptor (CTR/RAMP1 complex) with selectivity over the CGRP receptor (CLR/RAMP1), because its sequence shares greater structural homology with calcitonin receptor-stimulating peptides (CRSP) than with CGRP, directing it toward the CTR-containing AMY complexes.
Why it’s plausible
The AMY1 receptor (CTR+RAMP1) mediates the metabolic and satiety effects of amylin, and pramlintide (an amylin analog) is an approved drug for glycemic control. CRSP peptides, referenced explicitly in the literature chunks (Katafuchi 2003, 2004), bind CTR-containing complexes. Pep-05144's sequence CGNLSTCMLG at the N-terminus is structurally closer to calcitonin and CRSP than to CGRP (which has a different ring size and sequence). The metabolic framing in the subtitle and the metabolic tag are consistent with AMY1-mediated appetite and glucose regulation. The CGRP receptor (CLR/RAMP1) would not be expected to bind calcitonin-like peptides with high affinity because its extracellular domain is shaped by CLR rather than CTR.
Why it matters
AMY1 receptor agonism is a validated mechanism for weight loss and blood glucose control. If pep-05144 is an AMY1 agonist, it represents a new sequence scaffold distinct from pramlintide that could avoid pramlintide's injection-site precipitation problem and potentially show improved receptor residence time.
Plausibility.53
Novelty.23
Impact.57
Basis · grounding3 papers · 1 computed/note
[1]
paper
IUPHAR review covers pharmacology at CGRP, AM1, and AM2 receptors formed by CLR/RAMP complexes, and distinguishes these from CTR-based AMY receptors
doi: 10.1111/bph.14075
[2]
paper
Katafuchi 2003/2004 refs within the review describe CRSP isolation from porcine brain and its activity at CTR-based receptors
doi: 10.1111/bph.14075
[3]
sequenceCGNLSTCM at N-terminus with C1-C7 ring motif is characteristic of calcitonin/CRSP-class peptides rather than CGRP, which has a shorter ring (C2-C7 in CGRP)
[4]
paper
Axis hit describing allosteric modulation of CTR by RAMPs, relevant to AMY1 vs CTR selectivity distinction
doi: 10.1074/jbc.m115.713628
openupdated 2026-06-05

Does the loose, unstructured tail of this molecule cause it to detach from its receptor faster, and does that affect how useful it could be as a drug?

A peptide that releases its receptor quickly tends to cause less desensitisation over time, which could be an advantage for chronic conditions like obesity or type 2 diabetes where sustained daily dosing is needed. Understanding this structural detail guides how the molecule might be optimised for real-world use.

The hypothesis
The glycine-rich C-terminal segment (TSIGVGAP) of pep-05144 prevents stable helix formation in that region and results in a disordered tail that interacts with the extracellular loop 2 of CTR through non-helical contacts, distinct from the C-terminal helix seen in some calcitonin family analogs.
Why it’s plausible
Glycine is a helix breaker. The terminal IGVGAP contains glycine at two positions (G27 and G30), and valine and proline further constrain conformation. In calcitonin analogs, the C-terminal region typically contributes to binding affinity through hydrophobic interactions with receptor TMD residues. In amylin/CRSP family members, the C-terminal tail is more flexible. The VGAP sequence at the C-terminus is unusual and suggests a beta-turn or coil termination rather than a helix cap, which would alter the geometry of TMD engagement. This is consistent with the sequence being a designed (not naturally occurring) peptide.
Why it matters
Understanding whether the C-terminal tail is structured or disordered directly predicts receptor residence time and off-rate. A disordered C-terminal tail would confer faster dissociation and potentially lower potency but also reduced receptor downregulation, which may be advantageous for durable metabolic effects in chronic dosing.
Plausibility.43
Novelty.32
Impact.42
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceTSIGVGAP at positions 25-32 contains two glycines and a proline, strongly disfavoring alpha-helix formation in this segment
[2]
structureBoltz-2 structure computed (status level: computed via nvidia_nim_api); interface confidence not reported numerically but the computed structure can be evaluated for C-terminal helix content
[3]
paper
Delivery-formulation axis hit cites NMR solution structure of CGRP (Breeze et al. 1991), establishing that calcitonin family C-terminal regions have defined conformational behavior relevant to receptor engagement
doi: 10.1152/physrev.00034.2013
openupdated 2026-06-05

If this molecule works through a different brain circuit than GLP-1 drugs, could combining them produce better results than either alone?

GLP-1 drugs like semaglutide are effective but not sufficient for everyone. The combination of amylin-type and GLP-1 signalling is already showing promise in obesity research. If this peptide fills that amylin-type role with a novel structure, it could become part of a combination approach for people who need greater weight loss or glucose control than current drugs provide.

The hypothesis
Pep-05144 reduces food intake and improves insulin sensitivity in diet-induced obesity through AMY receptor-mediated activation of hindbrain satiety circuits, independently of GLP-1 receptor signaling.
Why it’s plausible
Amylin analogs act on area postrema and nucleus tractus solitarius AMY1 receptors to reduce meal size and slow gastric emptying; this mechanism is additive with GLP-1 receptor agonism as shown by tirzepatide-era combination studies. The subtitle explicitly frames the peptide as targeting the same body system as modern weight and blood-sugar drugs (GLP-1 agonists), suggesting the designers intended CTR/AMY axis engagement. If pep-05144 engages AMY1, its effects on body weight would be mechanistically distinct from and potentially synergistic with GLP-1 agonists. The FHTF motif in pep-05144 (positions 21-24) is present in calcitonin family members known to activate CTR in the brain.
Why it matters
Combination of AMY and GLP-1 signaling is the leading approach to obesity pharmacotherapy beyond current GLP-1 monotherapy. A novel AMY1-active scaffold that diverges from pramlintide in sequence could enable dual-agonist strategies with improved PK or allow CNS targeting formulations that pramlintide cannot achieve.
Plausibility.40
Novelty.18
Impact.55
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceFHTFPQ (positions 21-26) contains the FHTF motif found in calcitonin family members with CNS activity at CTR
[2]
paper
IUPHAR review covers calcitonin/CGRP family receptor distribution in brain and metabolic tissues relevant to satiety circuits
doi: 10.1111/bph.14075
[3]
noteSubtitle states peptide targets the same body system as modern weight and blood-sugar drugs, implying metabolic/obesity indication was the design intent
openupdated 2026-06-05

If this molecule only partially switches on the calcitonin receptor, could it still protect bone without causing the blood-calcium drops that full activation can trigger?

Therapeutic calcitonin can lower blood calcium too much, limiting its use. A partial activator could provide a gentler, more controlled effect on bone resorption with a lower risk of that side effect. This would matter for patients with osteoporosis who cannot tolerate full-strength calcitonin therapy.

The hypothesis
Pep-05144 binds the calcitonin receptor (CTR) as a partial agonist rather than full agonist because its C-terminal sequence (IGVGAP) lacks the proline-amide required for maximal CTR activation seen in salmon and human calcitonin.
Why it’s plausible
Calcitonin family peptides require a C-terminal amidated proline or equivalent residue for full efficacy at CTR; the terminal ...IGVGAP sequence of pep-05144 is not amidated and ends in a free carboxylate. Native salmon calcitonin (sCT) ends in Pro-NH2, and removal or substitution of the C-terminal amide reduces intrinsic efficacy without necessarily abolishing binding. The N-terminal disulfide ring (C1-C7 in this sequence, if the bridge forms) is preserved, which is the primary affinity determinant for CTR. Partial agonism at CTR is pharmacologically relevant because partial agonists can function as functional antagonists in tissues where endogenous calcitonin tone is high, while still producing signaling in low-tone states.
Why it matters
If pep-05144 is a CTR partial agonist, it could modulate bone resorption and calcium homeostasis with a ceiling effect that limits hypocalcemic adverse events, a long-standing limitation of therapeutic calcitonin. This would also inform whether metabolic effects (the peptide's stated framing) arise through CTR or through an AMY receptor complex.
Plausibility.39
Novelty.18
Impact.53
Basis · grounding1 paper · 2 computed/notes
[1]
sequenceC-terminal sequence IGVGAP is unamidated; no Pro-NH2 present, unlike native calcitonins which bear a C-terminal amide essential for full CTR agonism
[2]
sequenceC1 and C7 are both cysteine, consistent with the N-terminal disulfide ring that is the primary binding determinant for calcitonin at CTR
[3]
paper
IUPHAR review details structure-activity relationships of calcitonin family members at CTR, including the role of C-terminal amidation and N-terminal ring
doi: 10.1111/bph.14075
details expand to inspect
full evidence table2 metrics
metricvaluetool
ipTM 0.7279504537582397 boltz-2
ranking score 0.708127498626709 boltz-2
structural qualityopenfold3
metricvaluenote
gpde0.960global PDE — lower = better
disorderNaNfraction disordered
3-letter notation
Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Leu-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ser-Ile-Gly-Val-Gly-Ala-Pro
recipeboltz-2 1.0
parametervalue
modelboltz-2 1.0
weights
hardwarenvidia_nim_api
mlx version
python
random seed
msa strategynone
diffusion samples1
runtime
predicted bymlx@peptide
predicted at2026-04-24
citationbibtex
peptidemodel (2026). Calcitonin metabolic peptide (pep-05144, v1). PeptideModel. https://peptidemodel.com/card/pep-05144
@peptide{pep05144,
  sequence = {CGNLSTCMLGTYTQDLNKFHTFPQTSIGVGAP},
  target   = {glp-1r},
  author   = {peptidemodel},
  year     = {2026},
  status   = {computed}
}
related peptides 4 by signal overlap
references 1 papers
[1] supporting
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