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 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.
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Mark A
MA
Miller
Navdeep B
NB
Malkar
Diana
D
Severynse-Stevens
Kevin G
KG
Yarbrough
Mark J
MJ
Bednarcik
Robert E
RE
Dugdell
Monica E
ME
Puskas
Radha
R
Krishnan
Kenneth D
KD
James
D000284:Administration, Oral; D000595:Amino Acid Sequence; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D045283:Natriuretic Agents / Q000008:administration & dosage* / Q000737:chemistry* / Q000627:therapeutic use; D020097:Natriuretic Peptide, Brain / Q000008:administration & dosage* / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use
D045283:Natriuretic Agents; D020097:Natriuretic Peptide, Brain