Amphiphilic Conjugates of Human Brain Natriuretic Peptide Designed for Oral Delivery:  In Vitro Activity Screening

Congestive heart failure (CHF) is a complex syndrome involving altered neurohormonal levels and impaired cardiac and renal function. In recent years, intravenous administration of exogenous human brain-type natriuretic peptide (hBNP) has become an important therapy in treating patients with acutely...

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Bibliographic Details
Published in:Bioconjugate chemistry 2006-03, Vol.17 (2), p.267-274
Main Authors: Miller, Mark A, Malkar, Navdeep B, Severynse-Stevens, Diana, Yarbrough, Kevin G, Bednarcik, Mark J, Dugdell, Robert E, Puskas, Monica E, Krishnan, Radha, James, Kenneth D
Format: Article
Language:English
Subjects:
Administration, Oral
Amino Acid Sequence
Biochemistry
Heart failure
Heart Failure - drug therapy
Hormones
Humans
Molecular Sequence Data
Molecular Structure
Natriuretic Agents - administration & dosage
Natriuretic Agents - chemistry
Natriuretic Agents - therapeutic use
Natriuretic Peptide, Brain - administration & dosage
Natriuretic Peptide, Brain - chemistry
Natriuretic Peptide, Brain - genetics
Natriuretic Peptide, Brain - therapeutic use
Peptides
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Summary:Congestive heart failure (CHF) is a complex syndrome involving altered neurohormonal levels and impaired cardiac and renal function. In recent years, intravenous administration of exogenous human brain-type natriuretic peptide (hBNP) has become an important therapy in treating patients with acutely decompensated CHF. However, reports during the past year suggest that hBNP could play a prominent role in the chronic treatment of CHF patients as well. We are currently developing conjugates of hBNP suitable for oral delivery to provide a patient-friendly treatment option for chronic heart failure patients. In this report, we present in vitro activity results obtained from hBNP conjugates featuring a variety of rationally designed amphiphilic oligomers. Mapping studies revealed that the hydrophobic/hydrophilic balance of the oligomer impacted the regioselectivity of conjugation. Additionally, the regiochemistry and extent of conjugation had a significant impact on activity. Many monoconjugates retained activity comparable to native peptide and are currently under evaluation in subsequent in vivo screens.
ISSN:1043-1802
1520-4812
DOI:10.1021/bc0501000