Synthetic peptide analogs of lung surface protein SP-C

Details Synthetic peptide analogs of lung surface protein SP-C Synthetic peptide analogs of lung surface protein SP-C

1996-11-27

1999-02-23

Fitzgerald, David L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 2, 514 78, 530324, C07K 14785, A61K 3817

Patent

active

058744061

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The invention relates to polypeptides with pulmonary surfactant activity, processes for the preparation thereof and therapeutic compositions containing these.


PRIOR ART

The lungs of all vertebrates contain a mixture of substances which is referred to as "pulmonary surfactant". It has surface-active properties and reduces the surface tension in the alveolar region of the lungs to such an extent that collapse of the terminal regions of the airways on breathing out is avoided. This mixture of substances controls the surface tension in a dynamic manner so that the collapse, which is to be expected according to Laplace's theorem, of the small alveoli in favor of the larger ones is prevented by appropriate adjustment of the surface tension. The result of this is a well-balanced, histologically and physiologically stable structure of the lungs.
Pulmonary surfactant is secreted by the type II alveolar pneumocytes in the form of lamellar bodies. These are compact units of phospholipid bilayers with a high content of dipalmitoylphosphatidylcholine (DPPC) and phosphatidylglycerol (PG). Further essential components present in pulmonary surfactant are proteins referred to as SP-A, SP-B and SP-C. SP-A is a high molecular weight glycoprotein which plays a crucial part in controlling secretion.
The proteins SP-C and, to a smaller extent, SP-B assume the role of "thermodynamic catalysts" in forming the monomolecular surface film (the surfactant in the narrower sense). The presence of these proteins greatly speeds up the kinetics of spreading. Only this makes it possible to adjust, without delay, the surfactant composition to the particular surface tension requirements. These properties are reflected by the extremely hydrophobic nature of the proteins, especially of SP-C.
It has been possible to obtain, by extraction of pulmonary tissue or irrigation of animal lungs, surfactant preparations which show, both in physicochemical measuring equipment, such as in animal models, and on clinical use, the ability to compensate for a surfactant deficiency and thus are suitably, for example, for the treatment of infant respiratory distress syndrome (IRDS). However, these animal preparations have serious intrinsic weaknesses:
The composition of the phospholipids depends greatly on the animal species, health and nutritional state of the animal and can be compensated to only a limited extent by admixture of defined components. The content of surfactant proteins and the SP-B/SP-C ratio is subject to the same uncertainties. An additional factor is that the mixture employed for therapy also contains possible proteolytic breakdown products of the proteins or modified derivatives (for example by oxidation on methionine). On long-term use or administration of large amounts of surfactant as might be necessary, for example, in cases of adult respiratory distress syndrome (shock lung, ARDS) or in other fields of use, such as, for example, the utilization of surfactant as "entrainer" for other substances on pulmonary administration, the question of the supply of substance is open.
It is therefore obvious to solve these problems by preparing the proteins by genetic manipulation. Since recombinant proteins can, especially on use of bacterial expression systems, be prepared in virtually unlimited amounts, and the use of modern analytical methods and quality controls is possible, it is possible by using synthetic phospholipids to prepare a surfactant of exactly defined composition. This can be adjusted optimally to the therapeutic requirements.
The human protein SP-C (see formula I with A=H or Phe, S=Cys and C=Met), which is particularly important for the kinetics of spreading, consists in its central part exclusively of aliphatic, very hydrophobic amino acids such as valine, leucine and isoleucine. The length of this central part (amino acids 12-34) permits the peptide to be integrated into the monomolecular phospholipid film. In the Pro-Cys Cys-Pro sequence (position 3-6), the two Cys residues are thioesterified by palmitic acid

REFERENCES:
patent: 5385840 (1995-01-01), Benson et al.
patent: 5387746 (1995-02-01), Whitsett
patent: 5552161 (1996-09-01), Disse et al.
Glasser et al. (1988) J. Biol. Chem. 263: 10326-10331.
Longo et al. (1993) Science 261: 453-486.

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