Abemaciclib restricts HCMV replication by suppressing pUL97-mediated phosphorylation of SAMHD1

Syrigos, Georgios Vavouras; Feige, Maximilian; Dirlam, Alicia; Businger, Ramona; Gruska, Iris; Wiebusch, Lüder; Hamprecht, Klaus; Schindler, Michael

doi:10.1016/j.antiviral.2023.105689

Cited by 2 publications

(1 citation statement)

References 56 publications

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“…Recently, we characterized pharmacological inhibitors of cyclin-dependent kinases (CDKs) as very potent anti-HCMV investigational candidates and suggested CDK-directed targeting as a next-generation developmental strategy towards new antiviral small molecules [ 12 , 13 , 14 , 15 ]. In this ongoing line of research, we focused on both host CDKs, such as CDK7 (i.e., using the selective developmental inhibitor LDC4297 [ 16 ]), as well as the viral CDK ortholog pUL97 (vCDK; i.e., using the clinically approved maribavir/MBV and chemically distinct investigational pUL97 inhibitors [ 7 , 17 , 18 ]).…”

Section: Introductionmentioning

confidence: 99%

Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers

Wild,

Karner,

Eickhoff

et al. 2023

Pharmaceutics

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Despite the availability of currently approved antiviral drugs, infections with human cytomegalovirus (HCMV) still cause clinically challenging, sometimes life-threatening situations. There is an urgent need for enhanced anti-HCMV drugs that offer improved efficacy, reduced dosages and options for long-term treatment without risk of the development of viral drug resistance. Recently, we reported the pronounced anti-HCMV efficacy of pharmacological inhibitors of cyclin-dependent kinases (CDKs), in particular, the potential of utilizing drug synergies upon combination treatment with inhibitors of host CDKs and the viral CDK-like kinase pUL97 (vCDK/pUL97). Here, we expand this finding by further assessing the in vitro synergistic antiviral interaction between vCDK and CDK inhibitors towards HCMV as well as non-human cytomegaloviruses. An extension of this synergy approach was achieved in vivo by using the recombinant MCMV-UL97/mouse model, confirming the high potential of combination treatment with the clinically approved vCDK inhibitor maribavir (MBV) and the developmental CDK7 inhibitor LDC4297. Moreover, mechanistic aspects of this synergistic drug combination were illustrated on the levels of intracellular viral protein transport and viral genome replication. The analysis of viral drug resistance did not reveal resistance formation in the case of MBV + LDC4297 combination treatment. Spanning various investigational levels, these new results strongly support our concept, employing the great potential of anti-HCMV synergistic drug treatment.

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Section: Introductionmentioning

confidence: 99%

Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers

Wild,

Karner,

Eickhoff

et al. 2023

Pharmaceutics

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Targeted protein degradation: advances in drug discovery and clinical practice

Zhong,

Chang,

Xie

et al. 2024

Sig Transduct Target Ther

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Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell’s intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces challenges related to the properties of the drugs and their rational design. This review thoroughly explores the mechanisms and clinical advancements of TPD, from its initial conceptualization to practical implementation, with a particular focus on proteolysis-targeting chimeras and molecular glues. In addition, the review delves into emerging technologies and methodologies aimed at addressing these challenges and enhancing therapeutic efficacy. We also discuss the significant clinical trials and highlight the promising therapeutic outcomes associated with TPD drugs, illustrating their potential to transform the treatment landscape. Furthermore, the review considers the benefits of combining TPD with other therapies to enhance overall treatment effectiveness and overcome drug resistance. The future directions of TPD applications are also explored, presenting an optimistic perspective on further innovations. By offering a comprehensive overview of the current innovations and the challenges faced, this review assesses the transformative potential of TPD in revolutionizing drug development and disease management, setting the stage for a new era in medical therapy.

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Abemaciclib restricts HCMV replication by suppressing pUL97-mediated phosphorylation of SAMHD1

Cited by 2 publications

References 56 publications

Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers

Combined Treatment with Host-Directed and Anticytomegaloviral Kinase Inhibitors: Mechanisms, Synergisms and Drug Resistance Barriers

Targeted protein degradation: advances in drug discovery and clinical practice

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