Publikationsdatenbank

Development of a PROTAC-based targeting strategy provides a mechanistically unique mode of anti-cytomegalovirus activity (2021)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Hahn, Friedrich

Hamilton, Stuart T.

Wangen, Christina

Wild, Markus

Kicuntod, Jintawee

Brückner, Nadine

Follett, Jasmine E. L.

Herrmann, Lars

Kheimar, Ahmed (WE 5)

Kaufer, Benedikt B. (WE 5)

Rawlinson, William D.

Tsogoeva, Svetlana B.

Marschall, Manfred

Quelle

International journal of molecular sciences

Bandzählung: 22

Heftzählung: 23

Seiten: Artikel 12858

ISSN: 1422-0067

Sprache

Englisch

Verweise

URL (Volltext): https://www.mdpi.com/1422-0067/22/23/12858

DOI: 10.3390/ijms222312858

Pubmed: 34884662

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Human cytomegalovirus (HCMV) is a major pathogenic herpesvirus that is prevalent worldwide and it is associated with a variety of clinical symptoms. Current antiviral therapy options do not fully satisfy the medical needs; thus, improved drug classes and drug-targeting strategies are required. In particular, host-directed antivirals, including pharmaceutical kinase inhibitors, might help improve the drug qualities. Here, we focused on utilizing PROteolysis TArgeting Chimeras (PROTACs), i.e., hetero-bifunctional molecules containing two elements, namely a target-binding molecule and a proteolysis-inducing element. Specifically, a PROTAC that was based on a cyclin-dependent kinase (CDK) inhibitor, i.e., CDK9-directed PROTAC THAL-SNS032, was analyzed and proved to possess strong anti-HCMV AD169-GFP activity, with values of EC50 of 0.030 µM and CC50 of 0.175 µM (SI of 5.8). Comparing the effect of THAL-SNS032 with its non-PROTAC counterpart SNS032, data indicated a 3.7-fold stronger anti-HCMV efficacy. This antiviral activity, as illustrated for further clinically relevant strains of human and murine CMVs, coincided with the mid-nanomolar concentration range necessary for a drug-induced degradation of the primary (CDK9) and secondary targets (CDK1, CDK2, CDK7). In addition, further antiviral activities were demonstrated, such as the inhibition of SARS-CoV-2 replication, whereas other investigated human viruses (i.e., varicella zoster virus, adenovirus type 2, and Zika virus) were found insensitive. Combined, the antiviral quality of this approach is seen in its (i) mechanistic uniqueness; (ii) future options of combinatorial drug treatment; (iii) potential broad-spectrum activity; and (iv) applicability in clinically relevant antiviral models. These novel data are discussed in light of the current achievements of anti-HCMV drug development.