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Inaccurate Serelaxin Chemical Structure

Matthew J. DellaVecchia PhD

To the Editor:

I would like to comment on what appears to be an error in the October 2013 issue of P&T in the Drug Forecast article, entitled “Serelaxin, a ‘Breakthrough’ Investigational Intravenous Agent for Acute Heart Failure” (Volume 10, pages 606–611).

My concern has to do with the legend of Figure 1, “Structural formula of serelaxin. Available at: www.ama-assn.org/resources/doc/usan.” Specifically, the hyperlink and the structure of serelaxin are incomplete. The full link directs readers to a PDF document of the American Medical Association (AMA): http://ama-assn.org/resources/doc/usan/serelaxin.pdf.

Serelaxin is correctly referred to in the text as a recombinant form of human relaxin-2, a naturally occurring polypeptide, with a molecular formula of C256H408N74O74S8 (molecular weight: 5.96 kilodaltons or 5,960 g/mol). A more descriptive structural formula can be found at http://pubchem.ncbi.nlm.nih.gov/rest/chemical/71300755 (see new figure below).

RNL2 protein, human, also known as human relaxin II, relaxin 2, serelaxin, relaxin H2, and H2 relaxin.

Investigation of the structural formula section of the AMA reference (as well as others) reveals that serelaxin is an insulin-like peptide with a total of 65 amino acids forming an A and B chain with three disulfide bridges. Furthermore, one of the amino acids present in the sequence of serelaxin is that of l-pyroglutamic acid, present in the A chain of the serelaxin peptide at position 1. It is the structure of this amino acid alone, with a considerably more modest molecular formula of C5H7NO3 (molecular weight: 129 g/mol) that is displayed in Figure 1 of the Drug Forecast article.

Of all the amino acids in serelaxin, this particular amino acid is singled out in the AMA’s reference in the ‘structural formula’ section (just below the complete listing of the primary amino acid sequences for both the A and B chains of serelaxin) because it is a “modified residue.” l-pyroglutamic acid is a cyclized/lactam form of the more familiar glutamic acid.

Because lengthy peptide sequences are typically listed in standard single-letter amino acid code, the authors might have chosen to include the chemical structure of l-pyroglutamic acid in their article as a representative portion of the drug molecule. However, the legend for Figure 1 does not state this, nor is there any indication that this modified residue is chiefly responsible for the drug’s mechanism of action in the treatment of acute heart failure. So although it is indeed a part of serelaxin, the structure shown in Figure 1 is that of l-pyroglutamic acid, a single amino acid—not serelaxin, a polypeptide.

If a reader has simply adopted a “pictures and graphs”–only approach when reading this article, as many busy health professionals and scientists are prone to do, and if reading the main text of the article is avoided, Figure 1, as presented, may imply that serelaxin is a small-molecule drug, when in fact it is a considerably larger peptide drug. Peptides can differ greatly in terms of their oral bio-availability, compared with small-molecule drugs, in large part because of the presence of acid-sensitive peptide (amide) bonds. Such bonds are generally readily hydrolyzed at low pH in the stomach, thus destroying a peptide’s molecular structure and, hence, its biological action.

As the article states, serelaxin is administered intravenously, probably as a means to avoid this issue. Furthermore, a quick online search reveals that l-pyroglutamic acid, like many other amino acids, is readily available as an oral dietary supplement. Figure 1 in the Drug Forecast article may give the false impression that l-pyroglutamic acid is also beneficial for the treatment of acute heart failure.

In closing, while this chemical misrepresentation is likely a simple oversight and one that will probably not change any practitioner’s mind about serelaxin, it highlights the need for pharmacists to be mindful of accurately representing the structural and chemical properties of drug molecules.

Sincerely,

Matthew J. DellaVecchia, PhD
Associate Professor of Pharmaceutical Sciences–Medicinal Chemistry
Gregory School of Pharmacy
Palm Beach Atlantic University
West Palm Beach, Florida
Matthew_DellaVecchia@pba.edu