Sinapultide

Identification

Name
Sinapultide
Accession Number
DB11332
Description

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
Thumb
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

Pharmacology

Indication

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

Contraindications & Blackbox Warnings
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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.

TargetActionsOrganism
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.

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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

Products

International/Other Brands
AEROSURF
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
SurfaxinSinapultide (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)SuspensionEndotrachealDiscovery Health2013-11-012016-01-19US flag

Categories

Drug Categories
Classification
Not classified

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[[email protected]](NC(=O)[[email protected]@H](N)CCCCN)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CCCCN)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CCCCN)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CCCCN)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CC(C)C)C(=O)N[[email protected]@H](CCCCN)C(O)=O

References

General References
  1. 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. [PubMed:29121767]
  2. 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. [PubMed:16871629]
  3. Sinapultide, PubChem [Link]
  4. Sinapultide, Pharmacodia [Link]
  5. Sinapultide [Link]
  6. Surfactant respiratory therapy using Surfaxin/sinapultide [Link]
  7. Sinapultide - Windtree Therapeutics [Link]
  8. EMA Withdrawal Public Assessment Report [Link]
  9. FDA label for Surfaxin [Link]
  10. KL4 Surfactant, WindTree [Link]
ChemSpider
16742247
RxNav
1440288
ChEMBL
CHEMBL2103901

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentCystic Fibrosis (CF)1
2CompletedTreatmentHypoxemic Acute Respiratory Failure1
2RecruitingTreatmentRespiratory Distress Syndrome, Newborn1
2TerminatedPreventionChronic Lung Disease of Prematurity / Premature Births / Respiratory Distress Syndrome, Newborn1
2TerminatedTreatmentRespiratory Distress Syndrome1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SuspensionEndotracheal
Prices
Not Available
Patents
Not Available

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0125 mg/mLALOGPS
logP-0.37ALOGPS
logP5.44ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)3.68ChemAxon
pKa (Strongest Basic)10.9ChemAxon
Physiological Charge5ChemAxon
Hydrogen Acceptor Count28ChemAxon
Hydrogen Donor Count27ChemAxon
Polar Surface Area775.42 Å2ChemAxon
Rotatable Bond Count93ChemAxon
Refractivity671.78 m3·mol-1ChemAxon
Polarizability283.93 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

1. Lung epithelial cells
Kind
Group
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
References
  1. KL4 Surfactant, WindTree [Link]
  2. FDA label for Surfaxin [Link]

Drug created on December 03, 2015 09:52 / Updated on June 12, 2020 10:53

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