This is a first-in-human, phase I, open-label, monocenter, single dose-escalation study with 4 cohorts. The total trial duration for each participant will be not more than 98 d from screening to the end of the follow-up.
Twenty-four participants are planned to be enrolled in the trial. Each cohort may be expanded by up to 6 additional volunteers, resulting in a maximum of 48 participants possibly enrolled in the trial.
Ninety-six volunteers may need to be screened to include 48 volunteers.

Start Date25 Apr 2023

Sponsor / Collaborator

Innovative Molecules GmbH

NL-OMON50697

/ CompletedNot Applicable

A single-center, open-label, fixed-sequence Phase 1 trial to evaluate the effect of multiple doses of pritelivir on the pharmacokinetics of substrates for CYP2C9, CYP2B6, CYP3A4 and OATP2B1 - Pritelivir DDI study with celiprolol, flurbiprofen, bupropion and midazolam

Start Date18 Oct 2021

Sponsor / Collaborator

Aicuris Anti-Infective Cures AG

100 Clinical Results associated with DNA helicase/primase complex

100 Translational Medicine associated with DNA helicase/primase complex

0 Patents (Medical) associated with DNA helicase/primase complex

Literatures (Medical) associated with DNA helicase/primase complex

01 Jan 2024·microPublication biology

Separation of function mutants underline multiple roles of the Srs2 helicase/translocase in break-induced replication in Saccharomyces cerevisiae.

Article

Author: Liberi, Giordano ; Pellicioli, Achille ; Di Terlizzi, Matteo

All cells are commonly exposed to DNA double-strand breaks (DSBs), which must be properly repaired to avoid genomic instability. Break-Induced Replication (BIR) is a Homologous Recombination subpathway, which repairs DSBs resulting in mutagenesis, chromosome translocations and loss of heterozygosity. In budding yeast, the Srs2 DNA helicase/translocase plays both anti- and pro-recombination roles. Interestingly, Srs2 activities are required to support BIR completion. Here, we employ a interchromosomal BIR assay in S. cerevisiae to characterize Cdk1-dependent phosphorylation, ATPase and helicase activities of Srs2. Our results further expand our understanding of the multifaced role played by Srs2 in DSB recombination repair.

01 Aug 2022·BioEssays

WRN rescues replication forks compromised by a BRCA2 deficiency: Predictions for how inhibition of a helicase that suppresses premature aging tilts the balance to fork demise and chromosomal instability in cancer

Article

Author: Datta, Arindam ; Brosh, Robert M.

AbstractHereditary breast and ovarian cancers are frequently attributed to germline mutations in the tumor suppressor genes BRCA1 and BRCA2. BRCA1/2 act to repair double‐strand breaks (DSBs) and suppress the demise of unstable replication forks. Our work elucidated a dynamic interplay between BRCA2 and the WRN DNA helicase/exonuclease defective in the premature aging disorder Werner syndrome. WRN and BRCA2 participate in complementary pathways to stabilize replication forks in cancer cells, allowing them to proliferate. Whether the functional overlap of WRN and BRCA2 is relevant to replication at gaps between newly synthesized DNA fragments, protection of telomeres, and/or metabolism of secondary DNA structures remain to be determined. Advances in understanding the mechanisms elicited during replication stress have prompted the community to reconsider avenues for cancer therapy. Insights from studies of PARP or topoisomerase inhibitors provide working models for the investigation of WRN's mechanism of action. We discuss these topics, focusing on the implications of the WRN‐BRCA2 genetic interaction under conditions of replication stress.

01 May 2022·The FASEB Journal

Identifying Cellular and Viral Factor Recruitment to Herpes Simplex Virus Type 1 Replication Forks

Article

Author: Packard, Jessica E. ; Dembowski, Jill A.

Herpes simplex virus type 1 (HSV‐1) is a ubiquitous pathogen that replicates the 152kbp viral genome within the nucleus of host cells. Replication of the HSV‐1 genome is catalyzed by viral replication machinery consisting of a DNA polymerase (UL30), processivity factor (UL42), helicase‐primase complex, origin binding protein (UL9), and a single stranded DNA binding protein. Despite encoding a viral DNA polymerase processivity factor, we found that host Proliferating Cell Nuclear Antigen (PCNA) interacts with HSV‐1 DNA at replication forks and associates with viral DNA in a replication‐dependent manner. PCNA is a homotrimer that provides processivity to cellular DNA polymerases and selectively recruits DNA damage response and DNA repair factors to cellular replication forks. We therefore hypothesized that PCNA associates at viral replication forks to promote HSV‐1 replication while also tethering cellular DNA repair proteins to replicating viral DNA. To test this, we used two models to identify how associated factors change as a function of PCNA: a known PCNA inhibitor, PCNA‐I1, and a cell line that was engineered to inducibly express a shRNA targeting PCNA. We performed a technique adapted from isolation of proteins on nascent DNA (iPOND) to isolate HSV‐1 DNA from infected cells and identified associated viral and cellular proteins. Cells were infected and replicating viral DNA was selectively labeled with EdC. Labeled DNA was specifically and irreversibly tagged via the covalent attachment of biotin azide via click reaction. Biotin‐tagged DNA was purified on streptavidin‐coated beads and associated proteins were eluted and identified by mass spectrometry. As a complimentary approach, we also performed immunofluorescence (IF) to confirm iPOND data. We found that PCNA is associated with viral DNA despite treatment with PCNA‐I1, an observation that is consistent with IF imaging data. Viral replication proteins UL30, UL42, and UL9 decreased in the presence of PCNA‐I1. DNA damage response proteins such as mismatch repair proteins and RECQL both decreased up to 10‐fold. Of note, however, proteins that make up the MRN complex, a class of proteins that functions in DNA break repair, restart of stalled replication forks, and viral DNA infection, increased in response to PCNA‐I1 treatment. Given this data, PCNA may be involved in tethering viral replication proteins, cellular DNA repair proteins, and/or virion assembly proteins to viral replication forks.

News (Medical) associated with DNA helicase/primase complex

05 Jun 2024

·www.maruho.co.jp

Maruho and Hyphens Pharma Announce Exclusive License Agreement for Anti-herpes Virus Agent (INN: Amenamevir) in 10 ASEAN Countries

Osaka (Japan), June 5, 2024 - Maruho Co., Ltd. ("Maruho", Head Office: Osaka, Japan, President and CEO: Atsushi Sugita) and Hyphens Pharma Pte. Ltd., a subsidiary of Hyphens Pharma International Limited ("Hyphens", Head Office: Singapore, Chairman, Executive Director and CEO: Lim See Wah) announced that the two companies have entered into a license agreement under which Maruho will license to Hyphens the rights to develop and commercialize the anti-herpes virus agent amenamevir (JNN/INN), manufactured and marketed in Japan by Maruho, hereinafter referred to as "the product", in 10 ASEAN (Association of Southeast Asian Nations)*1 countries. Under the terms of the agreement, Maruho grants Hyphens an exclusive license to develop and market the product in 10 ASEAN countries. Hyphens will proceed with the development activities necessary to bring the product to market. After the product is commercialized, Hyphens will pay royalties to Maruho based on commercialization milestones. The product exhibits high antiviral activity against the varicella-zoster virus and the herpes simplex virus by inhibiting the activity of the helicase-primase complex, which is essential for viral DNA replication. In 2012, Maruho and Astellas Pharma Inc. executed a license agreement for the development and commercialization of the product. Maruho proceeded with development in Japan and the product was approved for the indications of "herpes zoster" in 2017 and "recurrent herpes simplex" in 2023. The product is currently manufactured and commercialized under the brand name of "Amenalief® Tablets 200 mg" in Japan. In its 5th Medium-Term Plan, initiated in October 2023, Maruho introduced a new business strategy termed the "Asia Dermatology Hub Concept." Maruho established a local subsidiary in China*2 in February 2024 and is promoting business development in Asian countries and regions. This agreement is an effort to realize business development in Asia and to respond to the unmet needs of patients in ASEAN countries who have limited options for herpes treatment. Maruho and Hyphens, which both specialize in dermatology, will work to bring smiles to the faces of patients suffering from viral skin diseases such as herpes zoster and herpes simplex in the countries and regions covered by this agreement. Note The information contained in this news release in regard to pharmaceutical and developmental products is not intended for the purpose of promotion, advertising or medical advice. (*1) Thailand, Indonesia, Malaysia, Philippines, Singapore, Vietnam, Brunei, Cambodia, Myanmar, Laos (*2) Establishment of a local subsidiary in China (February 2024) https://www.maruho.co.jp/english/information/20240222.html [References] Maruho Launches Anti-Herpes Virus Agent "Amenalief Tab. 200mg" in Japan (2017/09/02) https://www.maruho.co.jp/english/information/2017090702.html Maruho Receives Manufacturing and Marketing Approval for a Partial Change of the Indication and Dosage/Administration for Anti-herpes Virus Agent "Amenalief Tab. 200mg" for the Treatment of Recurrent Herpes Simplex in Japan (2023/02/24) https://www.maruho.co.jp/english/information/20230224.html About HyphensHyphens Pharma International Limited and its subsidiaries (the "Group") is Singapore's leading specialty pharmaceutical and consumer healthcare group, leveraging on its diverse footprint in ASEAN countries. The Group has a direct presence in Singapore, Vietnam, Malaysia, Indonesia, and the Philippines, and is supplemented by a marketing and distribution network covering 14 other markets. The Group's core business comprises Specialty Pharma Principals, Proprietary Brands, and Medical Hypermart & Digital. Besides marketing and selling a range of specialty pharmaceutical products in selected ASEAN countries through exclusive distributorship or licensing and supply agreements with brand principals mainly from Europe and the United States, the Group also develops, markets, and sells its own proprietary range of dermatological and health supplement products. For more information, please visit https://www.hyphensgroup.com/ About MaruhoMaruho Co., Ltd. has its head office in Osaka and leads Japan in research and development, manufacturing and commercialization of dermatological products. Founded in 1915, Maruho has 1,566 employees (as of the end of September 2023), and net sales were approximately 85.71 billion yen in its fiscal year ended September 30, 2023. With the mission "More smiles, brighter life for you.", Maruho aims to help realize a society where everyone can live with a smile. For more information, please visit www.maruho.co.jp/english/ Contact Information: Maruho Co., Ltd. Public Relations Group, Corporate Planning Dept. Tel：+81-(0)6-6371-8831 Fax：+81-(0)6-6371-8679 Email：kouhou@mii.maruho.co.jp

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