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An L-RNA-Based Aquaretic Agent That Inhibits Vasopressin in Vivo

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An L-RNA-Based Aquaretic Agent That Inhibits Vasopressin in Vivo An L-RNA-based aquaretic agent that inhibits vasopressin in vivo Werner G. Purschke, Dirk Eulberg, Klaus Buchner, Stefan Vonhoff, and Sven Klussmann* NOXXON Pharma AG, Max-Dohrn-Strasse 8-10, 10589 Berlin, Germany Edited by Jack Keene, Duke University, Durham, NC, and accepted by the Editorial Board February 2, 2006 (received for review November 7, 2005) A class of diuretic͞aquaretic agents based on mirror-image oligo- inadequately coupled to the decreased plasma osmolality (9), nucleotides (so-called Spiegelmers) has been identified. These but, as a consequence, patients show symptoms of chronic molecules directly bind and inhibit the neuropeptide vasopressin volume overload, hyponatremia, congestion, and increased sys- (AVP). AVP is the major regulatory component of body fluid temic vascular resistance (10). A central point in CHF is the homeostasis mediated through binding to the renal V2 receptor. progression of left ventricular dysfunction and chamber remod- Elevated plasma levels of AVP are implicated in several patholog- eling (11). AVP may be involved in these aspects of CHF because ical conditions, mainly cardiovascular diseases. In congestive heart AVP can induce structural changes in the myocardium through failure, AVP is part of a neuroendocrine imbalance that is respon- activation of the V1a receptor (12, 13). Elevated AVP levels are sible for progressive worsening of the disease. Employing in vitro also found in the syndrome of inappropriate antidiuretic hor- selection techniques, RNA aptamers that bind to the unnatural mone secretion (14) and late-stage liver cirrhosis (15), which D-configuration of AVP were isolated. The best aptamer displayed leads in both diseases to dilutional hyponatremia and hypoos- an affinity to D-AVP of Ϸ560 pM at 37°C. The corresponding molality. Through its mitogenic properties, AVP can also affect Spiegelmer, a 38-mer mirror-image oligonucleotide (L-RNA) termed the genesis of tumors. AVP and its receptors are expressed in all NOX-F37, inhibits vasopressin-dependent activation of V1a as well small cell lung carcinomas and breast cancer (16). In conclusion, as V2 receptors with IC50 values of 6.1 nM and 1 nM, respectively. a variety of severe human diseases exist where AVP seems to be NOX-F37 administered to healthy rats effectively neutralized AVP dysregulated and for which effective treatments are necessary. and increased diuresis dose-dependently for 24 h. The mode of Here we describe the development of a Spiegelmer that binds action was strictly aquaretic, i.e., the increase in urine volume was to AVP with high affinity and neutralizes its action. Spiegelmers not accompanied by an increase in electrolytes. These results are L-enantiomeric aptamers (17) that are identified through a clearly prove the in vivo efficacy of NOX-F37 and points out its SELEX-based (18) in vitro selection process that involves chiral potential as a drug in the treatment of diseases that are associated principles (19). First, the mirror-image configuration of AVP (all with body fluid overload. D-amino acids) is synthesized. A combinatorial nucleic acid library is screened to identify aptamers that bind to the all-D- aptamer ͉ congestive heart failure ͉ diureses ͉ water homeostasis ͉ AVP. Lastly, an individual aptamer sequence is synthesized in its Spiegelmer corresponding mirror-image configuration to give a Spiegelmer (L-oligonucleotide) that binds to the natural AVP. Spiegelmers he cyclic nonapeptide vasopressin (AVP) is a neurohormone have been identified already to bind to a variety of different Tthat is synthesized in the hypothalamus and stored in the peptide and protein targets (20–22). The mirror-image config- hypophysis from where it is released into the circulation (1). uration confers excellent biostability to Spiegelmers without the AVP is also known as antidiuretic hormone because its main need for further modifications. peripheral function is the maintenance of volume and osmolality We report the identification of a 38-mer RNA aptamer that of body fluids by regulating the free water reabsorption in the binds to AVP with an extraordinarily low dissociation constant kidneys. Under physiological concentrations, AVP acts vasocon- of 560 pM at 37°C. The corresponding Spiegelmer NOX-F37 strictive. AVP’s actions are mediated through specific G protein- inhibits AVP signaling in cell culture at the V2 and the V1a coupled receptors (2). The V receptor, mainly expressed on receptor with IC50 values of 1 and 6.1 nM, respectively. After 2 systemic administration NOX-F37 efficiently induces diuresis in cells of the basolateral membrane of the collecting duct in the a rat model, demonstrating its potential in neutralizing AVP’s kidneys, mediates the antidiuretic effect via enhanced cAMP action in vivo. levels (3). As a result, aquaporin channels are inserted into the cytoplasma membranes, and the transcription of aquaporin Results mRNA is induced. The V1a receptor, mainly expressed on D Identification of -AVP-Binding RNA Sequences. The in vitro selec- PHARMACOLOGY vascular smooth muscle cells and on cells of the myocardium, tion process to identify high-affinity RNA sequences binding to exerts vasoconstrictive effects through the second messengers D-AVP was divided into two parts: an automation-based stan- inositoltrisphosphate and diacylglycerol. Subsequently, intracel- ϩ dard selection (23) followed by a manually performed high- lular Ca2 is mobilized from the endoplasmic reticulum, and ϩ ϩ ϩ stringency protocol that included mutagenic steps within the Ca2 channels as well as Na ͞H exchangers are activated (4). amplification step. The selection was started with a library of In addition to vasoactive effects, binding of AVP to the V 1a Ϸ2.4 ϫ 1015 different RNA molecules and individual aptamer receptor also stimulates cell growth and proliferation in vascular sequences were identified after 16 selection rounds. Alignment smooth muscle cells through activation of the mitogen-activated protein kinase pathway (5). AVP release into the circulation is tightly regulated by osmo- Conflict of interest statement: All authors are employed by the biotechnology company receptors in the hypothalamus and baroreceptors in the heart NOXXON Pharma; none of the authors owns significant stock of the company. and large arteries. Whereas osmoreceptors respond to small This paper was submitted directly (Track II) to the PNAS office. J.K. is a guest editor invited changes (1%) in osmolality, baroreceptors respond only to by the Editorial Board. significant variations (10%) in blood volume and pressure (6, 7). Abbreviations: AVP, vasopressin; CHF, congestive heart failure; ITC, isothermal titration In congestive heart failure (CHF) patients, AVP plasma levels calorimetry; PEG, polyethylene glycol. are approximately two to three times higher than in healthy *To whom correspondence should be addressed. E-mail: [email protected]. subjects (8). It is not well understood why the AVP release is © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0509663103 PNAS ͉ March 28, 2006 ͉ vol. 103 ͉ no. 13 ͉ 5173–5178 Downloaded by guest on September 28, 2021 Fig. 1. AVP binding sequences. (A) 134-A9 is the best sequence that resulted from automated selection whereas 157-B4 was obtained as the best sequence after applying a mutagenic high-stringency (mhs) protocol; other variants of the mhs protocol are listed in Supporting Appendix, which is published as supporting information on the PNAS web site. (B) Consensus motif of AVP-binding sequences composed of terminal helical regions, two G rich boxes and an AU-rich (6–9 nt) region. The four G stretches in box2 are shown in bold. of the sequences revealed one family of relatives that differ by Although the sequences that resulted from the high stringency point mutations (data not shown). selection were not much different from the originally identified Truncation of the primer binding sites resulted in aptamers molecules, comparative ranking showed a significant improve- consisting of 47–49 nucleotides. The best binding sequence ment in binding affinity. In a competitive binding assay with an 134-A9 (Fig. 1A) was synthesized in its L-configuration. It excess of nonlabeled RNA, the best aptamer from the high inhibits L-AVP-induced cAMP formation in cell culture with an stringency selection, 157-B4, was determined to bind Ϸ12-fold IC50 of Ϸ50 nM (data not shown). To identify sequences with better to biotinylated D-AVP than 134-A9 (data not shown). even higher binding affinity, the enriched pool of round 16 was subjected to additional 13 selection rounds with increased Optimization of Aptamer 157-B4 by Site-Directed Modification with stringency, and a mutagenic amplification protocol was applied Hexaethyleneglycol. Because shorter oligonucleotides are easier in six selection rounds. Sequencing revealed further variants of and more cost effectively produced, we truncated the best the originally identified family. An alignment unveiled a 46- to binding aptamer 157-B4 (47-mer) further by replacing nucleo- 49-nt consensus motif (Fig. 1B; CLUSTAL X; ref. 24) that contains tides with a hexaethyleneglycol linker (26). The sequence vari- distinct secondary structure elements as predicted by a software ability of the AU-rich region was the most promising target to algorithm (ref. 25; Fig. 2). The 5Ј and 3Ј end of the sequences are introduce the linker (Fig. 2). Indeed, all different variants in self-complementary (Helix 1 and Helix 2) and seem to form a which up to seven
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