Article
Virology
Jintawee Kicuntod, Sewar Alkhashrom, Sigrun Hage, Benedikt Diewald, Regina Muller, Friedrich Hahn, Peter Lischka, Heinrich Sticht, Jutta Eichler, Manfred Marschall
Summary: This study investigates the oligomeric interaction of HCMV core NEC and the antiviral activity of targeted inhibitors, suggesting the oligomeric binding pattern and drug-accessible complex as validated antiviral drug targets. The research provides insights into the formation of HCMV core NEC and the potential for developing new antiviral strategies.
Article
Chemistry, Medicinal
Sewar Alkhashrom, Jintawee Kicuntod, Katharina Stillger, Tamara Luetzenburg, Christian Anzenhofer, Ines Neundorf, Manfred Marschall, Jutta Eichler
Summary: The study identifies a peptide that can interfere with human cytomegalovirus infection and inhibit the interaction of viral proteins pUL50 and pUL53, indicating its potential as a target for new antiviral drugs.
Article
Cell Biology
Julia Tillmanns, Sigrun Haege, Eva Maria Borst, Julia Wardin, Jan Eickhoff, Bert Klebl, Sabrina Wagner, Christina Wangen, Friedrich Hahn, Eileen Socher, Manfred Marschall
Summary: This study demonstrates the importance of the human cytomegalovirus (HCMV) core NEC for viral replication and the potential for targeting this determinant using covalently NEC-binding warhead compounds.
Article
Virology
Jintawee Kicuntod, Sigrun Haege, Friedrich Hahn, Heinrich Sticht, Manfred Marschall
Summary: The nucleo-cytoplasmic capsid egress of herpesviruses is a unique regulated process that ensures the efficiency of viral replication and release. Recent studies have highlighted the functional importance of oligomerization in the HCMV-specific nuclear egress complex (NEC), which is both phosphorylation-dependent and sensitive to antiviral kinase inhibitors.
Article
Cell Biology
Sigrun Haege, Nicole Buescher, Victoria Pakulska, Friedrich Hahn, Annie Adrait, Steffi Krauter, Eva Maria Borst, Ursula Schloetzer-Schrehardt, Yohann Coute, Bodo Plachter, Manfred Marschall
Summary: The regulation of the nucleocytoplasmic release of herpesviral capsids is defined by the process of nuclear egress, with pUL50 playing a key role in recruiting various factors for vesicular transport pathway and supporting the distortion of the nuclear envelope.
Article
Cell Biology
Josephine Loesing, Sigrun Haege, Martin Schuetz, Sabrina Wagner, Julia Wardin, Heinrich Sticht, Manfred Marschall
Summary: Herpesviruses replicate their genomes and assemble their capsids in the host cell nucleus. To progress towards morphogenesis in the cytoplasm, herpesviruses evolved the strategy of nuclear egress as a highly regulated process of nucleo-cytoplasmic capsid transition. The study identified cross-viral interactions in the formation of the nuclear egress complex (NEC) and provided insights into potential targets for the development of NEC-directed inhibitory small molecules.
Article
Pharmacology & Pharmacy
Jintawee Kicuntod, Sigrun Haege, Josephine Loesing, Serli Kopar, Yves A. Muller, Manfred Marschall
Summary: The nucleocytoplasmic capsid egress of herpesviruses like the human cytomegalovirus (HCMV) is a uniquely regulated process. The core nuclear egress complex (NEC) of HCMV, represented by the pUL50-pUL53 heterodimer, has been validated as a novel target for antiviral strategies. Interfering with the hook-into-groove interaction of pUL50-pUL53 prevents NEC formation and limits viral replication efficiency.
ANTIVIRAL RESEARCH
(2023)
Article
Virology
Dipanwita Mitra, Mohammad H. Hasan, John T. Bates, Gene L. Bidwell, Ritesh Tandon
Summary: A peptide targeting pp150nt, pep-CR2, was found to significantly reduce HCMV virus growth with minimal impact on cell viability. The peptide specifically interferes with the pp150-capsid binding interface, sequestering pp150 in the nucleus and disrupting its loading onto capsids. Additionally, pep-CR2 effectively inhibits MCMV infection in cell culture, suggesting its potential as an antiviral agent.
Article
Microbiology
Juanbin Yin, Shasha Wang, Shanhui Ren, Zhengji Liang, Junwei Ge, Yuefeng Sun, Xiangping Yin, Xiangwei Wang
Summary: TMP269, a small molecular inhibitor of IIa histone deacetylase, has been found to play a vital role in cancer therapeutic. This study discovered that TMP269 treatment can significantly inhibit the replication of RABV virus without significant cytotoxicity. It was also found that TMP269 can reduce viral titers and protein levels of RABV at an early stage in the viral life cycle. RNA sequencing data revealed that immune-related pathways and autophagy-related genes were downregulated after RABV infection treated with TMP269. Further exploration showed that autophagy enhances RABV replication, while TMP269 can inhibit autophagy to decrease RABV replication. These findings provide a novel treatment strategy for rabies.
FRONTIERS IN MICROBIOLOGY
(2023)
Article
Virology
Christina Funk, Debora Marques da Silveira e Santos, Melanie Ott, Verena Raschbichler, Susanne M. Bailer
Summary: Herpes simplex virus type 1 nucleocapsids are released from the host nucleus through a process called nuclear egress, which is facilitated by two viral proteins - pUL34 and pUL31. Importantly, a functional bipartite nuclear localization signal (NLS) has been identified within pUL34, contributing to its proper subcellular localization and interaction with pUL31 for nuclear egress complex formation and viral replication.
Review
Virology
Veronica Sanchez, William Britt
Summary: The assembly of human cytomegalovirus involves changes in cellular architecture, metabolism, protein trafficking, and cellular homeostatic functions. The nuclear egress of HCMV nucleocapsids follows a pathway similar to other members of the herpesvirus family, and the virus encodes viral functions that exploit cellular functions to overcome barriers and bridge the nuclear membrane. This review provides an overview of our understanding of HCMV egress, with a focus on the more well-studied α-herpesviruses, HSV-1 and PRV.
Review
Chemistry, Multidisciplinary
Hailei Su, Feng Zhou, Ziru Huang, Xiaohua Ma, Kathiresan Natarajan, Minchuan Zhang, Yong Huang, Haibin Su
Summary: This article summarizes and analyzes recent studies on the molecular mechanisms of promising antiviral drugs for COVID-19, focusing on viral targets such as spike glycoprotein and host proteases, aiming to inspire new ideas for drug design and optimization in the future.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Ranim El Baba, Sebastien Pasquereau, Sandy Haidar Ahmad, Franck Monnien, Marine Abad, Frederic Bibeau, Georges Herbein
Summary: Mounting evidence suggests that human cytomegalovirus (HCMV) may be an oncogenic virus, as it has been found in malignant gliomas. The oncogenic proteins EZH2 and Myc have been correlated with glioma grade. This study provides experimental evidence that HCMV can reprogram mature human astrocytes into CMV-Elicited Glioblastoma Cells (CEGBCs) with glioblastoma-like traits. These CEGBCs exhibit spheroid formation and invasiveness, suggesting a role for HCMV in the transformation and invasion processes. Clinical strains of HCMV isolated from glioblastoma patients transformed human astrocytes into CEGBCs with upregulated EZH2 and Myc. These findings highlight the importance of Myc and EZH2 in the pathophysiology of astrocytic brain tumors and suggest new therapeutic strategies.
Article
Pharmacology & Pharmacy
Nikolaos Karantzelis, Michalis Petropoulos, Valeria De Marco, David A. Egan, Alexander Fish, Evangelos Christodoulou, David W. Will, Joe D. Lewis, Anastassis Perrakis, Zoi Lygerou, Stavros Taraviras
Summary: DNA replication initiation requires the loading of MCM2-7 complexes at the origins of replication during G1. Replication licensing is crucial for chromatin to be competent for DNA replication and its regulation is important for preventing abnormal DNA replication and genomic instability. CDT1 is a critical factor in replication licensing and it is controlled by redundant mechanisms involving Geminin, an inhibitor of CDT1. Abnormal expression of CDT1 and Geminin has been linked to tumorigenesis in vivo and is observed in various human tumors. This study developed an in vitro assay for screening small-molecule inhibitors targeting the CDT1/Geminin protein complex. The most potent compound, AF615, was found to specifically inhibit Geminin binding to CDT1 both in vitro and in cells. AF615 also induced DNA damage, inhibited DNA synthesis, and selectively reduced viability in cancer cell lines, and this effect was dependent on CDT1. The findings suggest that AF615 could be a useful tool for studying the role of the CDT1/Geminin protein complex in replication licensing and origin firing.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Yaxin Li, Cody M. Orahoske, Werner J. Geldenhuys, Asmita Bhattarai, Abboud Sabbagh, Viharika Bobba, Fatma M. Salem, Wenjing Zhang, Girish C. Shukla, Justin D. Lathia, Bingcheng Wang, Bin Su
Summary: Compound I, an HSP27 inhibitor, effectively induces AR degradation in GBM cells via the proteasomal pathway, selectively inhibiting the growth of AR-overexpressed GBM cells. These findings suggest that targeting HSP27 to induce AR degradation in GBM shows promise as a novel treatment approach.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Rebecca Hoffmann, Tamara Ruegamer, Johanna Schaubaecher, Anette Rohrhofer, Peter Kirmess, Karen M. Fiebig, Barbara Schmidt, Jutta Eichler
Summary: Co-infection with HPgV-1 can benefit disease progression in HIV-1-infected individuals, with the peptide P6-2 showing inhibitory activity against HIV-1 by interacting with the envelope glycoprotein gp120.
Article
Virology
Jintawee Kicuntod, Sewar Alkhashrom, Sigrun Hage, Benedikt Diewald, Regina Muller, Friedrich Hahn, Peter Lischka, Heinrich Sticht, Jutta Eichler, Manfred Marschall
Summary: This study investigates the oligomeric interaction of HCMV core NEC and the antiviral activity of targeted inhibitors, suggesting the oligomeric binding pattern and drug-accessible complex as validated antiviral drug targets. The research provides insights into the formation of HCMV core NEC and the potential for developing new antiviral strategies.
Article
Multidisciplinary Sciences
Mark Kriegel, Hanna J. Wiederanders, Sewar Alkhashrom, Jutta Eichler, Yves A. Muller
Summary: The application of PROSS server algorithms enabled the development of variant ERPRS* with 24 amino acid substitutions, leading to improved production rates, crystallization, and thermal stability. Despite 10% amino acid substitutions, ERPRS* preserved the allosteric regulatory behaviors of nuclear receptors, suggesting promise for developing novel modulators targeting hER alpha.
SCIENTIFIC REPORTS
(2021)
Article
Immunology
Antonia Sophia Peter, Edith Roth, Sebastian R. Schulz, Kirsten Fraedrich, Tobit Steinmetz, Dominik Damm, Manuela Hauke, Elie Richel, Sandra Mueller-Schmucker, Katharina Habenicht, Valentina Eberlein, Leila Issmail, Nadja Uhlig, Simon Dolles, Eva Gruner, David Peterhoff, Sandra Ciesek, Markus Hoffmann, Stefan Pohlmann, Paul F. McKay, Robin J. Shattock, Roman Wolfel, Eileen Socher, Ralf Wagner, Jutta Eichler, Heinrich Sticht, Wolfgang Schuh, Frank Neipel, Armin Ensser, Dirk Mielenz, Matthias Tenbusch, Thomas H. Winkler, Thomas Grunwald, Klaus Uberla, Hans-Martin Jack
Summary: TRIANNI mice were used to generate 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein, and identified two clusters of neutralizing antibodies targeting different regions of the spike protein. These neutralizing antibodies significantly reduced viral spread and protected mice from SARS-CoV-2-induced weight loss, showing potential for therapy and prophylaxis of COVID-19.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Microbiology
Johannes Schweininger, Myriam Scherer, Franziska Rothemund, Eva-Maria Schilling, Sonja Worz, Thomas Stamminger, Yves A. Muller
Summary: Cytomegaloviruses have evolved a species-specific IE1 protein tertiary structure to effectively bind and inactivate the important cellular restriction factor PML, forming a barrier to cross-species transmission. The highly conserved fold of IE1 maximizes the efficacy of PML targeting in a species-specific manner, illustrating the co-evolution of viruses and their hosts.
Article
Biochemistry & Molecular Biology
Susanne Huhmann, Elisabeth K. Nyakatura, Anette Rohrhofer, Johann Moschner, Barbara Schmidt, Jutta Eichler, Christian Roth, Beate Koksch
Summary: This study evaluated a fluorinated peptide inhibitor which showed the ability to block HIV-1 infection of target cells at nanomolar levels, indicating that fluorinated amino acids are suitable tools for the development of novel peptide therapeutics.
Article
Clinical Neurology
Isabelle Aillaud, Senthilvelrajan Kaniyappan, Ram Reddy Chandupatla, Lisa Marie Ramirez, Sewar Alkhashrom, Jutta Eichler, Anselm H. C. Horn, Markus Zweckstetter, Eckhard Mandelkow, Heinrich Sticht, Susanne Aileen Funke
Summary: The study suggests that ISAD1 and related D-amino acid peptides may be helpful in the treatment of Alzheimer's disease by inhibiting Tau fibrillization and preventing its toxicity.
ALZHEIMERS RESEARCH & THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Johannes Schweininger, Mark Kriegel, Sigrun Hage, Marcus Conrad, Sewar Alkhashrom, Josephine Losing, Sigrid Weiler, Julia Tillmanns, Claudia Egerer-Sieber, Andrea Decker, Tihana Lenac Rovis, Jutta Eichler, Heinrich Sticht, Manfred Marschall, Yves A. Muller
Summary: The formation of the core nuclear egress complex (NEC) in varicella-zoster virus (VZV) displays subfamily-specific features. Understanding these features is crucial for developing drugs that target multiple herpesviruses.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Lucas Weissenborn, Elie Richel, Helena Hueseman, Julia Welzer, Silvan Beck, Simon Schaefer, Heinrich Sticht, Klaus Ueberla, Jutta Eichler
Summary: Using the structure of a de novo designed miniprotein (LCB1) in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, truncated peptide variants of LCB1 were generated and characterized. These variants, which retained virus neutralizing potency against different SARS-CoV-2 variants of concern (VOC), showed even stronger antiviral activity than the full-length peptide. The cyclic variant of the two-helix peptides exhibited significantly improved proteolytic stability, making it a better candidate for SARS-CoV-2 therapy. These peptides can also be chemically modified to further stabilize them against degradation and enhance their virus neutralizing capacity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Virology
Franziska Rothemund, Myriam Scherer, Eva-Maria Schilling, Johannes Schweininger, Yves A. Muller, Thomas Stamminger
Summary: The study analyzed the functions of human cytomegalovirus (CMV) immediate early 1 (IE1) protein and rat CMV IE1 (rIE1) protein, and found that their interactions with cellular proteins PML and FEN1 were species-specific. It was also discovered that both IE1 proteins can antagonize human STAT2, but different regions of the viral proteins were involved in the interaction. Additionally, the study revealed that the binding of PML, FEN1, and STAT2 was conserved between primate and rodent proteins, but rIE1 lacked chromatin tethering function.
Article
Chemistry, Medicinal
Sewar Alkhashrom, Jintawee Kicuntod, Katharina Stillger, Tamara Luetzenburg, Christian Anzenhofer, Ines Neundorf, Manfred Marschall, Jutta Eichler
Summary: The study identifies a peptide that can interfere with human cytomegalovirus infection and inhibit the interaction of viral proteins pUL50 and pUL53, indicating its potential as a target for new antiviral drugs.
Article
Biology
Manuel Deubler, Lucas Weissenborn, Simon Leukel, Anselm H. C. Horn, Jutta Eichler, Heinrich Sticht
Summary: PG16 is a broadly neutralizing antibody that binds to the gp120 subunit of the HIV-1 Env protein. Sulfation of Tyr100H in the CDRH3 residue enhances interactions with gp120 and stabilizes the protein-protein contacts and interactions with the gp120 glycan shield. PG16-CDRH3 can be used as a template to develop peptide mimetics as potential inhibitors of HIV invasion.