A Randomized, Adaptive-design, Dose-finding Study to Assess the Antiviral Efficacy and Safety of NIM811 Administered in Combination With the Standard of Care (SOC) in Relapsed Patients Infected With HCV Genotype-1

This is a study designed to identify a dose of NIM811 that has a good safety profile, is well tolerated when co-administered with SOC, and provides a clinically meaningful effect in viral load reduction compared to SOC alone. This information will be used to support doses selected for future studies.

Start Date01 Sep 2009

Sponsor / Collaborator

Novartis Pharmaceuticals Corp.

100 Clinical Results associated with [N-MeIle4]-cyclosporin

100 Translational Medicine associated with [N-MeIle4]-cyclosporin

100 Patents (Medical) associated with [N-MeIle4]-cyclosporin

111

Literatures (Medical) associated with [N-MeIle4]-cyclosporin

01 Oct 2024·Protein science : a publication of the Protein Society

Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.

Article

Author: Di Matteo, Adele ; Jiménez-Faraco, Eva ; Catucci, Gianluca ; Dominici, Paola ; Sadeghi, Sheila J ; Hermoso, Juan A ; Astegno, Alessandra ; Favretto, Filippo ; Travaglini-Allocatelli, Carlo

Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X-ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein-ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response.

01 Aug 2023·NatureQ1 · CROSS-FIELD

TRIM5α restricts poxviruses and is antagonized by CypA and the viral protein C6.

Q1 · CROSS-FIELD

Article

Author: Smith, Geoffrey L ; Richardson, Samuel ; Albarnaz, Jonas D ; Sreekumar, Meghna ; Lu, Yongxu ; Zhao, Yiqi

Human tripartite motif protein 5α (TRIM5α) is a well-characterized restriction factor for some RNA viruses, including HIV^1-5; however, reports are limited for DNA viruses^6,7. Here we demonstrate that TRIM5α also restricts orthopoxviruses and, via its SPRY domain, binds to the orthopoxvirus capsid protein L3 to diminish virus replication and activate innate immunity. In response, several orthopoxviruses, including vaccinia, rabbitpox, cowpox, monkeypox, camelpox and variola viruses, deploy countermeasures. First, the protein C6 binds to TRIM5 via the RING domain to induce its proteasome-dependent degradation. Second, cyclophilin A (CypA) is recruited via interaction with the capsid protein L3 to virus factories and virions to antagonize TRIM5α; this interaction is prevented by cyclosporine A (CsA) and the non-immunosuppressive derivatives alisporivir and NIM811. Both the proviral effect of CypA and the antiviral effect of CsA are dependent on TRIM5α. CsA, alisporivir and NIM811 have antiviral activity against orthopoxviruses, and because these drugs target a cellular protein, CypA, the emergence of viral drug resistance is difficult. These results warrant testing of CsA derivatives against orthopoxviruses, including monkeypox and variola.

01 Oct 2020·iScienceQ2 · CROSS-FIELD

Inhibition of the Activity of Cyclophilin A Impedes Prolactin Receptor-Mediated Signaling, Mammary Tumorigenesis, and Metastases

Q2 · CROSS-FIELD

ArticleOA

Author: Hakim, Shawn ; Clevenger, Charles V ; Craig, Justin M ; Koblinski, Jennifer E

Prolactin (PRL) and its receptor (PRLr) play important roles in the pathogenesis of breast cancer. Cyclophilin A (CypA) is a cis-trans peptidyl-prolyl isomerase (PPI) that is constitutively associated with the PRLr and facilitates the activation of the tyrosine kinase Jak2. Treatment with the non-immunosuppressive prolyl isomerase inhibitor NIM811 or CypA short hairpin RNA inhibited PRL-stimulated signaling, breast cancer cell growth, and migration. Transcriptomic analysis revealed that NIM811 inhibited two-thirds of the top 50 PRL-induced genes and a reduction in gene pathways associated with cancer cell signaling. In vivo treatment of NIM811 in a TNBC xenograft lessened primary tumor growth and induced central tumor necrosis. Deletion of CypA in the MMTV-PyMT mouse model demonstrated inhibition of tumorigenesis with significant reduction in lung and lymph node metastasis. The regulation of PRLr/Jak2-mediated biology by NIM811 demonstrates that a non-immunosuppressive prolyl isomerase inhibitor can function as a potential breast cancer therapeutic.

100 Deals associated with [N-MeIle4]-cyclosporin

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Indication	Highest Phase	Country/Location	Organization	Date
Chronic hepatitis C genotype 1	Phase 2	TW	Novartis Pharmaceuticals Corp.	01 Sep 2009
Chronic hepatitis C genotype 1	Phase 2	BE	Novartis Pharmaceuticals Corp.	01 Sep 2009
Chronic hepatitis C genotype 1	Phase 2	AU	Novartis Pharmaceuticals Corp.	01 Sep 2009
Chronic hepatitis C genotype 1	Phase 2	ES	Novartis Pharmaceuticals Corp.	01 Sep 2009
Chronic hepatitis C genotype 1	Phase 2	US	Novartis Pharmaceuticals Corp.	01 Sep 2009
Chronic hepatitis C genotype 1	Phase 2	PR	Novartis Pharmaceuticals Corp.	01 Sep 2009
Hepatitis C	Phase 2	CN	Novartis Pharma AG	12 Jun 2009
Hepatitis C	Preclinical	CN	Beijing Novartis Pharma Co. Ltd.	12 Jun 2009
Chronic hepatitis C genotype 1	Discovery	DE	Novartis Pharmaceuticals Corp.	01 Sep 2009

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