Hannover, Germany
Hannover, Germany

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Zirafi O.,University of Ulm | Kim K.-A.,University of Ulm | Standker L.,University of Ulm | Standker L.,PHARIS Biotec GmbH | And 36 more authors.
Cell Reports | Year: 2015

CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation. © 2015 The Authors.


Forssmann W.-G.,Leibniz University of Hanover | Forssmann W.-G.,VIRO Pharmaceuticals GmbH and Co. KG | Forssmann W.-G.,Pharis Biotec GmbH | The Y.-H.,Leibniz University of Hanover | And 20 more authors.
Science Translational Medicine | Year: 2010

To infect host cells, most enveloped viruses must insert a hydrophobic fusion peptide into the host cell membrane. Thus, fusion peptides may be valuable targets for developing drugs that block virus entry. We have shown previously that a natural 20-residue fragment of a1-antitrypsin, designated VIRus-Inhibitory Peptide (VIRIP), that binds to the gp41 fusion peptide of HIV-1 prevents the virus from entering target cells in vitro. Here, we examine the efficacy of 10-day monotherapy with the optimized VIR-576 derivative of VIRIP in treatment-naïve, HIV-1-infected individuals with viral RNA loads of ≥10,000 copies per ml. We report that at the highest dose (5.0 grams per day), intravenous infusion of VIR-576 reduced the mean plasma viral load by 1.23 log10 copies per ml without causing severe adverse effects. Our results are proof of concept that fusion peptide inhibitors suppress viral replication in human patients, and offer prospects for the development of a new class of drugs that prevent virus particles from anchoring to and infecting host cells.


PubMed | Red Cross, Hannover Medical School, UMR7242, University of Pennsylvania and 7 more.
Type: Journal Article | Journal: Cell reports | Year: 2015

CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.3.2-3 | Award Amount: 6.60M | Year: 2012

Major advances in HIV/AIDS treatment regimens have fundamentally altered the natural history of the disease and sharply reduced HIV-related morbidity and mortality in countries where such treatments are accessible. The most notable advance is the use of combination antiretroviral therapy or ART. However, ART is unable to achieve virus eradication or sterilizing cure. Indeed, in most cases, viral rebound is observed after ART interruption. Thus, life-long treatment is currently needed to control HIV. Drug resistance, cumulative side effects and high cost, represent major drawbacks of such treatments. The persistence of HIV in treated patients results from the establishment of a viral reservoir insensitive to ART and poorly visible to the immune system. Thus, understanding HIV persistence and developing drugs able to flush out HIV, in order to achieve viral eradication or sterilizing cure remain outstanding challenges. Two main lines of research are being proposed. The first starts from the recent discovery by partners of this consortium of the immune-modulator Samhd1 as the cellular factor restricting HIV-1 infection in myeloid cells. We will explore a role for Samhd1 in immune activation and inflammation, and its impact on the balance between viral replication and persistence. To understand further HIV persistence, we will study the molecular mechanisms underlying post-integrative latency. The second aims at identifying and optimizing novel naturally occurring inducers of HIV reactivation. Additionally, a novel non-human primate model will be developed, allowing the study of viral persistence in vivo by tracking latently-infected cells. The project aims at (i) increasing knowledge on the contribution of immune activation and inflammation to HIV persistence (ii) deciphering the cellular and molecular mechanisms of viral persistence (iii) translating this basic knowledge into novel targets to achieve a cure for HIV/AIDS.


Dobrivojevic M.,University of Zagreb | Sindic A.,University of Zagreb | Edemir B.,Universitatsklinikum Munster | Kalweit S.,Pharis Biotec GmbH | And 2 more authors.
American Journal of Physiology - Cell Physiology | Year: 2012

In this study, the interaction of natriuretic peptides (NP) and bradykinin (BK) signaling pathways was identified by measuring membrane potential (Vm) and intracellular Ca2+ using the patch-clamp technique and flow cytometry in HEK-293 cells. BK and NP receptor mRNA was identified using RT-PCR. BK (100 nM) depolarized cells activating bradykinin receptor type 2 (B2R) and Ca2+-dependent Cl- channels inhibitable by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 10 μM). The BK-induced Ca2+ signal was blocked by the B2R inhibitor HOE 140. [Des-Arg9]-bradykinin, an activator of B1R, had no effect on intracellular Ca2+. NP [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin] depolarized HEK-293 cells inhibiting K+ channels. ANP, urodilatin, BNP [binding to natriuretic peptide receptor (NPR)-A] and 8-bromo- (8-Br)-cGMP inhibited the BK-induced depolarization while CNP (binding to NPR-Bi) failed to do so. The inhibitory effect on BKtriggered depolarization could be reversed by blocking PKG using the specific inhibitor KT 5823. BK-stimulated depolarization as well as Ca2+ signaling was completely blocked by the phospholipase C (PLC) inhibitor U-73122 (10 nM). The inositol 1,4,5-trisphosphate receptor blocker 2-aminoethoxydiphenyl borate (2-APB; 50 μM) completely inhibited the BK-induced Ca2+ signaling. UTP, another activator of the PLC-mediated Ca2+ signaling pathway, was blocked by U-73122 as well but not by 8-Br-cGMP, indicating an intermediate regulatory step for NP via PKG in BK signaling such as regulators of G-protein signaling (RGS) proteins. When RGS proteins were inhibited by CCG-63802 in the presence of BK and 8-Br-cGMP, cells started to depolarize again. In conclusion, as natural antagonists of the B2R signaling pathway, NP may also positively interact in pathological conditions caused by BK. © 2012 the American Physiological Society.


Peigneur S.,Catholic University of Leuven | Beress L.,Leibniz University of Hanover | Beress L.,Pharis Biotec GmbH | Moller C.,Florida Atlantic University | And 4 more authors.
FASEB Journal | Year: 2012

APETx3, a novel peptide isolated from the sea anemone Anthopleura elegantissima, is a naturally occurring mutant from APETx1, only differing by a Thr to Pro substitution at position 3. APETx1 is believed to be a selective modulator of human ether-á-go-go related gene (hERG) potassium channels with a Kd of 34 nM. In this study, APETx1, 2, and 3 have been subjected to an electrophysiological screening on a wide range of 24 ion channels expressed in Xenopus laevis oocytes: 10 cloned voltage-gated sodium channels (NaV 1.2-NaV1.8, the insect channels DmNa V1, BgNaV1-1a, and the arachnid channel VdNaV1) and 14 cloned voltagegated potassium channels (KV1.1-K V1.6, KV2.1, KV3.1, KV4.2, K V4.3, KV7.2, KV7.4, hERG, and the insect channel Shaker IR). Surprisingly, the Thr3Pro substitution results in a complete abolishment of APETx3 modulation on hERG channels and provides this toxin the ability to become a potent (EC50 276 nM) modulator of voltage-gated sodium channels (NaVs) because it slows down the inactivation of mammalian and insect NaV channels. Our study also shows that the homologous toxins APETx1 and APETx2 display promiscuous properties since they are also capable of recognizing NaV channels with IC50 values of 31 nM and 114 nM, respectively, causing an inhibition of the sodium conductance without affecting the inactivation. Our results provide new insights in key residues that allow these sea anemone toxins to recognize distinct ion channels with similar potency but with different modulatory effects. Furthermore, we describe for the first time the target promiscuity of a family of sea anemone toxins thus far believed to be highly selective. © FASEB.


Patent
Pharis Biotec Gmbh | Date: 2012-08-03

A process for preparing human relaxin-2 having the following amino acid sequence: A chain: B chain: comprising the following steps: providing the amino acids necessary for the synthesis of the A and B chains with usual protective groups, wherein the cysteines are employed as trityl-protected amino acids (L-Cys(Trt)-OH); effecting a chromatographic purification of the individual chains A and B after the solid state synthesis; followed by the simultaneous folding and combination of the individual chains A and B in ammonium hydrogencarbonate buffer at pH 7.9 to 8.4; and subsequent purification of the relaxin-2 formed.


Patent
Pharis Biotec GmbH | Date: 2014-04-30

An N-terminally protected peptide having the sequence wherein X is a group protecting the N-terminal of the peptide.


A peptide of the formula R^(1)-NH-HAEGTFTSDVSSYLEGQAAKEFIAWLVK-CONR^(2)R^(3 )wherein R=H or an organic compound comprising from 1 to 10 carbon atoms and R^(2 )R^(3)=independently H or an alkyl group of 1 to 4 carbon atoms; or certain analogues of said GLP-1 peptide can be used for the treatment and prophylaxis of heart ischemia-reperfusion injury

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