Sinapultide

Identification

Summary

Sinapultide is a synthetic lung surfactant used to treat infant respiratory distress syndrome.

Generic Name

Sinapultide

DrugBank Accession Number

DB11332

Background

Sinapultide (also known as KL4 peptide) is a synthetic protein used to mimic human lung surfactant protein B.⁴ This protein has a weight of 2469.40.⁴

Sinapultide is a 21-residue peptide made up of lysine (K) and leucine (L) residues with the sequence KLLLLKLLLLKLLLLKLLLLK (KL4), in aqueous dispersion with the phospholipids DPPC (dipalmitoylphosphatidylcholine), POPG (palmitoyloleoyl-phosphatidylglycerol), and palmitic acid, to create the drug lucinactant.⁸

The product was originally developed by the Scripps Research Institute, then licensed to Windtree Therapeutics.⁴ Windtree Therapeutics plans a phase III trial for Respiratory distress syndrome in 2018.⁷

Respiratory distress syndrome (RDS) is a major cause of mortality and morbidity in preterm infants. Surfactant replacement therapy has been commonly used to prevent and treat RDS in these newborns and is now a standard of care. First-generation synthetic surfactants that were previously used, such as Exosurf did not contain any surfactant protein. This large disadvantage was overcome with animal-derived surfactant products which contain specific proteins but are limited, but must be derived from animal sources. This has led to the development of newer synthetic surfactants such as lucinactant (Surfaxin), which contains sinapultide. Phase 3 clinical trials with Surfaxin show promising results with similar efficacy as animal-derived surfactants while avoiding the use of animal-origin products.⁶

Windtree is currently developing aerosolized KL4 surfactant to treat RDS in premature infants, and thereafter, to potentially address a range of indications in neonatal, pediatric and adult critical care patient populations.¹⁰

Type

Small Molecule

Groups

Approved

Structure

Similar Structures

Weight: Average: 2469.45
Monoisotopic: 2467.830403408
Chemical Formula: C₁₂₆H₂₃₈N₂₆O₂₂

Synonyms

Sinapultida
Sinapultide
Sinapultidum

External IDs

ATI 01
ATI-01
DSC-104
KL-4
KL4
RWJ 45652
RWJ-45652

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Pharmacology

Indication

Infant respiratory distress syndrome ⁴, ⁸, ⁹, ¹⁰.

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Pharmacodynamics

Windtree’s KL4 surfactant technology produces a synthetic surfactant that is structurally similar to human pulmonary surfactant and contains a proprietary synthetic peptide KL4 (sinapultide), cost a 21-amino acid peptide that is formulated to mimic the essential attributes of the human surfactant protein B (SP-B). This protein is one of four surfactant proteins and is the most important for the adequate function of the respiratory system. Windtree has demonstrated in pre-clinical studies that KL4 surfactant may possess certain other beneficial properties, including alteration of the inflammatory process, antimicrobial properties as well as non-immunogenicity ¹⁰.

Mechanism of action

Endogenous pulmonary surfactant lowers surface tension at the air-liquid interface of the alveolar surfaces during respiration and stabilizes the alveoli against collapse at resting transpulmonary pressures. A deficiency of pulmonary surfactant in premature infants results in RDS. Surfaxin, the drug in which this protein is included, compensates for the deficiency of surfactant and restores surface activity to the lungs of these infants ⁹.

To explore the mechanisms of protection that this sinapultide offers against RDS, in vitro assays were performed with human and murine endothelial cell monolayers, and polymorphonuclear leukocyte (PMN) transmigration in the presence or absence of KL(4)-surfactant or lipid controls was studied. Based on morphology, histopathology, white blood cell count, percentage of PMNs, and protein concentration in bronchoalveolar lavage fluid, the results that showed KL(4)-surfactant, blocked neutrophil influx into alveoli and thus prevented lung injury. Additionally, in vitro assays demonstrated KL(4)-surfactant decreased neutrophil transmigration at the endothelial cell level. KL(4)-surfactant diminished inflammation and lung permeability when compared with controls in both mouse models of lung injury. Evidence suggests the anti-inflammatory mechanism of the KL(4)-peptide is achieved through inhibition of PMN transmigration through the endothelium ².

Target	Actions	Organism
ALung epithelial cells	agonist	Humans

Absorption

Administered directly to the lung, where biophysical effects occur at the terminal airways and alveolar surface. No human pharmacokinetic studies have been done to characterize the absorption, distribution, metabolism, or elimination of this drug ⁹.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

Not Available

Route of elimination

Not Available

Half-life

Not Available

Clearance

Not Available

Adverse Effects

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Toxicity

If respiration, ventilation, or oxygenation is clearly affected after an accidental overdose, aspirate as much of the suspension as possible and provide the infant with supportive treatment ⁹.

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: Not Available

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International/Other Brands

AEROSURF

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Surfaxin	Sinapultide (0.862 mg/1mL) + 1-palmitoyl-2-oleoyl-sn-glycero-3-(phospho-rac-(1-glycerol)), sodium salt (7.50 mg/1mL) + Colfosceril palmitate (22.50 mg/1mL) + Palmitic Acid (4.05 mg/1mL)	Suspension	Endotracheal	Discovery Health	2013-11-01	2016-01-19

Chemical Identifiers

UNII: 040X3AX99T
CAS number: 138531-07-4
InChI Key: QSIRXSYRKZHJHX-TWXHAJHVSA-N
InChI: InChI=1S/C126H238N26O22/c1-69(2)53-90(137-106(153)85(132)43-33-38-48-127)114(161)145-98(61-77(17)18)122(169)149-99(62-78(19)20)118(165)141-91(54-70(3)4)110(157)133-86(44-34-39-49-128)107(154)138-95(58-74(11)12)115(162)146-103(66-82(27)28)123(170)150-100(63-79(21)22)119(166)142-92(55-71(5)6)111(158)134-87(45-35-40-50-129)108(155)139-96(59-75(13)14)116(163)147-104(67-83(29)30)124(171)151-101(64-80(23)24)120(167)143-93(56-72(7)8)112(159)135-88(46-36-41-51-130)109(156)140-97(60-76(15)16)117(164)148-105(68-84(31)32)125(172)152-102(65-81(25)26)121(168)144-94(57-73(9)10)113(160)136-89(126(173)174)47-37-42-52-131/h69-105H,33-68,127-132H2,1-32H3,(H,133,157)(H,134,158)(H,135,159)(H,136,160)(H,137,153)(H,138,154)(H,139,155)(H,140,156)(H,141,165)(H,142,166)(H,143,167)(H,144,168)(H,145,161)(H,146,162)(H,147,163)(H,148,164)(H,149,169)(H,150,170)(H,151,171)(H,152,172)(H,173,174)/t85-,86-,87-,88-,89-,90-,91-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-/m0/s1
IUPAC Name: (2S)-6-amino-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-6-amino-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-6-amino-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-6-amino-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2,6-diaminohexanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]hexanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]hexanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]hexanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]-4-methylpentanamido]hexanoic acid
SMILES: CC(C)C[C@H](NC(=O)[C@@H](N)CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(O)=O

References

General References

Qiu Y, Chow MYT, Liang W, Chung WWY, Mak JCW, Lam JKW: From Pulmonary Surfactant, Synthetic KL4 Peptide as Effective siRNA Delivery Vector for Pulmonary Delivery. Mol Pharm. 2017 Dec 4;14(12):4606-4617. doi: 10.1021/acs.molpharmaceut.7b00725. Epub 2017 Nov 17. [Article]
Kinniry P, Pick J, Stephens S, Jain D, Solomides CC, Niven R, Segal R, Christofidou-Solomidou M: KL4-surfactant prevents hyperoxic and LPS-induced lung injury in mice. Pediatr Pulmonol. 2006 Oct;41(10):916-28. doi: 10.1002/ppul.20468. [Article]
Sinapultide, PubChem [Link]
Sinapultide, Pharmacodia [Link]
Sinapultide [Link]
Surfactant respiratory therapy using Surfaxin/sinapultide [Link]
Sinapultide - Windtree Therapeutics [Link]
EMA Withdrawal Public Assessment Report [Link]
FDA label for Surfaxin [Link]
KL4 Surfactant, WindTree [Link]

External Links

ChemSpider: 16742247
RxNav: 1440288
ChEMBL: CHEMBL2103901

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
2	Completed	Treatment	Acute Lung Injury/Acute Respiratory Distress Syndrome (ARDS) / Coronavirus Disease 2019 (COVID‑19)	1
2	Completed	Treatment	Cystic Fibrosis (CF)	1
2	Completed	Treatment	Hypoxemic Acute Respiratory Failure	1
2	Completed	Treatment	Respiratory Distress Syndrome	2
2	Terminated	Prevention	Chronic Lung Disease of Prematurity / Premature Births / Respiratory Distress Syndrome, Newborn	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Suspension	Endotracheal

Prices

Not Available

Patents

Not Available

Properties

State

Not Available

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0125 mg/mL	ALOGPS
logP	-0.37	ALOGPS
logP	5.44	Chemaxon
logS	-5.3	ALOGPS
pKa (Strongest Acidic)	3.68	Chemaxon
pKa (Strongest Basic)	10.9	Chemaxon
Physiological Charge	5	Chemaxon
Hydrogen Acceptor Count	28	Chemaxon
Hydrogen Donor Count	27	Chemaxon
Polar Surface Area	775.42 Å²	Chemaxon
Rotatable Bond Count	93	Chemaxon
Refractivity	671.78 m³·mol^-1	Chemaxon
Polarizability	283.93 Å³	Chemaxon
Number of Rings	0	Chemaxon
Bioavailability	0	Chemaxon
Rule of Five	No	Chemaxon
Ghose Filter	No	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features