Cyclotheonamide A
Also known as: CTN‑A, Cyclotheonamide A
Source Cyclotheonamide A at Peptiology
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Summary
Cyclotheonamide A (CtA) is a cyclic pentapeptide isolated from marine sponges of the genus Theonella. In laboratory studies it acts as a slow‑binding inhibitor of several trypsin‑like serine proteases, most notably human alpha‑thrombin and bovine trypsin. The compound is used in research to explore protease inhibition and the molecular basis of coagulation, but it has not progressed to clinical use.
Mechanism of Action
CtA binds the active site of serine proteases through a Pro‑Arg motif that occupies the S1 specificity pocket and forms a two‑strand antiparallel β‑sheet with the Ser214‑Gly216 segment. Its α‑keto amide group acts as a transition‑state analogue, forming a tetrahedral hemiketal with the catalytic Ser195 oxygen. Additional aromatic stacking between the hydroxyphenyl group of CtA and Trp60D of thrombin stabilises the complex, while variations in surrounding enzyme residues modulate affinity for different proteases.
What the Research Shows
Crystallographic studies resolved CtA complexes with human α‑thrombin (1.7 Å) and bovine β‑trypsin (2.0 Å), revealing a common binding orientation but enzyme‑specific contacts that explain higher trypsin potency. Kinetic analyses report Ki values of 1.0 nM for thrombin and 0.2 nM for trypsin, with slower but measurable inhibition of plasmin, factor Xa and t‑PA (Ki 12–50 nM). Dose‑dependent prolongation of thrombin, activated partial thromboplastin and prothrombin times was observed in vitro. Synthetic analogues explored the S3 subsite and the importance of the α‑keto and olefin groups, yet structure‑activity relationships proved less predictable than expected.
Reported Benefits
CtA provides a potent and selective tool for inhibiting trypsin‑like serine proteases, especially trypsin, enabling detailed mechanistic studies of coagulation cascades and protease function. Its well‑characterised binding interactions serve as a template for designing novel anticoagulant leads and for probing the structural determinants of protease specificity in biochemical assays.
Limitations of the Evidence
Despite strong inhibition of trypsin, CtA is only a moderate thrombin inhibitor (reported Ki ranging from 0.18 µM to 1 nM), limiting its utility as a direct anticoagulant. Structure‑activity relationships for analogues remain unclear, and synthesis of the macrocyclic peptide is complex. All data derive from in‑vitro experiments; no animal or clinical evaluations exist, so efficacy and safety in living systems are unknown.
Safety Considerations
In vitro assays show that CtA dose‑dependently doubles clotting times, indicating a potential for bleeding if used systemically. No toxicology or in‑vivo safety data are available, and off‑target inhibition of other serine proteases (e.g., plasmin, factor Xa) could disrupt normal hemostasis. Caution is advised when interpreting its effects beyond controlled laboratory conditions.
How It Is Administered
Research applications have employed CtA via intravenous delivery in cell‑based or plasma assays, typically dissolved in aqueous buffers. No specific formulation details are provided in the literature, and the compound is not formulated for oral or other routes of administration.
Routes of Administration
Goals & Uses
- antithrombotic therapyCardiovascularLow
Contraindications
No contraindications recorded yet.
Adverse Effects
No adverse effects recorded yet.
Drug Interactions
No drug interactions recorded yet.
Population Constraints
No population constraints recorded yet.
Regulatory Status
No regulatory status recorded yet.
Evidence & Sources
- Journal ArticleLowGanesh V, et al.1996-01-01T00:00:00.000000Z
- Journal ArticleLowMaryanoff BE, et al.1995-01-01T00:00:00.000000Z
- Journal ArticleLowLewis SD, et al.1993-01-01T00:00:00.000000Z
- Journal ArticleLowMaryanoff BE, et al.1993-01-01T00:00:00.000000Z
Frequently Asked Questions
What type of molecule is cyclotheonamide A?
Cyclotheonamide A is a cyclic pentapeptide natural product isolated from marine sponges of the genus Theonella. Its macrocyclic structure includes a Pro‑Arg motif and an α‑keto amide group that confer protease‑inhibitory activity.
Which enzymes does cyclotheonamide A inhibit?
CtA inhibits several trypsin‑like serine proteases. It is most potent against trypsin (Ki ≈ 0.2 nM) and also inhibits human α‑thrombin (Ki reported between 1 nM and 0.18 µM), plasmin, factor Xa and tissue‑type plasminogen activator with Ki values in the low‑nanomolar to tens‑nanomolar range.
How does cyclotheonamide A bind to thrombin?
CtA occupies thrombin’s S1 pocket with its Arg residue, forms a β‑sheet with the Ser214‑Gly216 segment, and its α‑keto amide creates a hemiketal with the catalytic Ser195. An aromatic stacking interaction between CtA’s hydroxyphenyl group and Trp60D of thrombin further stabilises the complex.
Has cyclotheonamide A been tested in humans?
No. All published data are limited to in‑vitro enzymatic assays, crystallography, and synthetic analogue studies. There are no animal studies or clinical trials reported for CtA.
What are the main research uses of cyclotheonamide A?
CtA is used as a molecular probe to study serine protease inhibition, to elucidate structural determinants of thrombin and trypsin binding, and as a lead scaffold for designing new anticoagulant or protease‑inhibitor candidates in medicinal chemistry.
What is Cyclotheonamide A?
Cyclotheonamide A (CtA) is a cyclic pentapeptide isolated from marine sponges of the genus Theonella. In laboratory studies it acts as a slow‑binding inhibitor of several trypsin‑like serine proteases, most notably human alpha‑thrombin and bovine trypsin. The compound is used in research to explore protease inhibition and the molecular basis of coagulation, but it has not progressed to clinical use.
What is Cyclotheonamide A used for?
Cyclotheonamide A is educationally associated with: antithrombotic therapy. Educational only — not medical advice.
How is Cyclotheonamide A administered?
Recorded routes of administration: Intravenous.