Nesiritide (Natrecor): heart-failure relief drug
A lab-made copy of the heart's own stress hormone that widens blood vessels and helps clear fluid from the lungs during a heart-failure crisis; FDA-approved drug.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Nesiritide (brand name Natrecor) is a lab-made copy of a heart hormone called B-type natriuretic peptide (BNP) that the body releases when the heart is overstretched. Given as an intravenous infusion in hospital, it was used to treat acute decompensated heart failure — the crisis state where a failing heart can no longer keep fluid out of the lungs. The drug is recombinant human BNP: the amino acid sequence is identical to the BNP the heart itself secretes (Mills 2002, Congestive Heart Failure; Dorsch 2006, Pharmacotherapy). The 32-residue chain folds into a ring closed by an intramolecular disulfide bond between the two cysteines (Cys10 and Cys26), and that ring is the part that engages the natriuretic peptide receptor — without it the molecule is inactive; the ring is not visible in the raw 1-letter sequence.
History
Nesiritide was approved by the FDA in August 2001 as the first new parenteral agent for heart failure in more than a decade (Mills 2002; Noviasky 2007). Early enthusiasm rested on the VMAC trial, which compared intravenous nesiritide with nitroglycerin in patients hospitalised for decompensated heart failure and reported faster relief of pulmonary congestion (VMAC, JAMA 2002).
The story turned in 2005. Two pooled analyses by Sackner-Bernstein and colleagues raised the possibility that nesiritide increased the risk of worsening renal function (Sackner-Bernstein, Circulation 2005) and of short-term death (Sackner-Bernstein, JAMA 2005). Editorials at the time — including Topol's "Nesiritide — Not Verified" (NEJM 2005) — argued that the drug had been approved and adopted on a thinner evidence base than the heart-failure community had assumed. Use fell sharply.
To settle the question the manufacturer ran ASCEND-HF, a 7,141-patient randomised trial of nesiritide versus placebo on top of standard care (O'Connor 2011, NEJM; Hernandez 2009, American Heart Journal). It found no improvement in death or rehospitalisation at 30 days and only a small effect on dyspnoea that did not meet the prespecified clinically meaningful threshold. Topol's accompanying editorial titled the episode "The Lost Decade of Nesiritide" (Topol 2011, NEJM). The manufacturer (Janssen Pharmaceuticals) announced discontinuation of nesiritide manufacture in February 2018; the drug is no longer commercially produced.
What it does
In someone with a failing heart, blood vessels are constricted, the heart is overfilled, and the kidneys are retaining salt and water. Nesiritide pushes back on all three: it relaxes both veins and arteries (so the heart pumps against less resistance and is less overfilled), and it tells the kidneys to excrete more sodium and water. The net result is a rapid fall in pulmonary capillary wedge pressure and systemic vascular resistance, with a rise in stroke volume, and no direct stimulation of heart rate — unlike older inotropes such as dobutamine (Elkayam 2002; Mills 2002).
Because its action does not go through beta-adrenergic signalling, it remains effective in patients on beta-blockers (Abraham 2005). Subjectively, the main clinical benefit shown in trials has been faster relief of breathlessness over the first 6–24 hours of hospitalisation (O'Connor 2011).
Evidence
- Human: Tested in tens of thousands of patients across VMAC (vs nitroglycerin, JAMA 2002), FUSION I and FUSION II (serial outpatient infusions, Yancy 2004; Yancy 2008), ROSE AHF (low-dose strategy, Wan 2016) and the definitive 7,141-patient ASCEND-HF trial (O'Connor, NEJM 2011). Multiple meta-analyses have since concluded that nesiritide does not reduce mortality in acute decompensated heart failure (Yan 2014; Zhao 2020).
- Animal / in vitro: The receptor pharmacology of BNP (and therefore of nesiritide, its recombinant copy) has been mapped in vascular, renal, adrenal and brain tissues, where it raises intracellular cGMP and produces vasodilation and natriuresis (Elkayam 2002).
Known effects
- Vasodilation (venous and arterial) — Documented haemodynamically; the basis of the original FDA approval (VMAC, JAMA 2002).
- Reduction in pulmonary capillary wedge pressure — Demonstrated in VMAC and replicated across subsequent trials (Mills 2002).
- Short-term symptom relief (dyspnoea) — Small but statistically significant benefit at 6–24 hours in ASCEND-HF (O'Connor 2011).
- Diuresis / natriuresis — Mechanistically expected and observed, though the renal effect has been controversial across trials (Gottlieb 2013; van Deursen 2014).
- No mortality benefit — Confirmed by ASCEND-HF and subsequent meta-analyses (O'Connor 2011; Yan 2014).
Safety signals
The two specific safety signals that defined nesiritide's clinical trajectory are worsening renal function and short-term mortality, both raised in 2005 pooled analyses (Sackner-Bernstein, Circulation 2005; Sackner-Bernstein, JAMA 2005). ASCEND-HF, designed in part to adjudicate those signals in a single large trial, did not confirm an increase in 30-day mortality but did not show a survival benefit either (O'Connor 2011). Renal effects across trials have been inconsistent and appear partly dose-dependent (van Deursen 2014). Hypotension is the most consistent on-treatment adverse event, reflecting the drug's mechanism (Dorsch 2006; Arora 2006).
Regulatory status
- US: FDA-approved August 2001 (Natrecor) for intravenous treatment of acutely decompensated congestive heart failure in patients with dyspnoea at rest or with minimal activity (Mills 2002, Congestive Heart Failure; Noviasky 2007, Pharmacotherapy). Following ASCEND-HF, professional society guidelines no longer recommend it as a routine vasodilator for acute heart failure. Janssen Pharmaceuticals discontinued manufacture in February 2018; not currently commercially available in the United States.
- WADA: Not on the Prohibited List; not relevant to performance enhancement.
Related peptides
Nesiritide is one of three mammalian natriuretic peptide hormones that have entered clinical use as agonists at the natriuretic peptide receptors:
- Atrial natriuretic peptide (ANP) — the atrial counterpart; the recombinant analog carperitide is marketed in Japan for acute heart failure.
- C-type natriuretic peptide (CNP) — endothelial; basis for vosoritide, approved for achondroplasia.
(No verified internal pep-XXXXX cards for these analogs are linked here; cross-links can be added at curation if matching cards exist.)
▸3-letter notation
▸citationbibtex
@peptide{pep04434,
sequence = {SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH},
target = {},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}