Novel cytomegalovirus-inhibitory compounds of the class pyrrolopyridines show a complex pattern of target binding that suggests an unusual mechanism of antiviral activity
Introduction
Human cytomegalovirus (HCMV, family Herpesviridae) is one of eight human herpesviruses that establish life-long latency in the host. HCMV infection has a high prevalence worldwide with seropositivity rates that range between 40% and 95% depending on socioeconomic factors. Usually, primary infection of persons with a competent immune system is either asymptomatic or results in mild, mononucleosis-like symptoms. However, life-threatening disease can be caused in patients with a compromised, suppressed or underdeveloped immune system (Mocarski et al., 2013). Moreover, congenital abnormalities as well as developmental delay can occur when HCMV infection takes place during pregnancy. About 10% of newborns with congenital infection are symptomatic at birth (Hamilton et al., 2015; Rawlinson et al., 2017). Not only primary infection but also reactivation represents a challenging medical issue, particularly in the field of anti-tumor chemotherapy and transplantation medicine. So far, therapy options are limited and no HCMV vaccine is available so far. Antiviral therapy is currently mainly based on inhibitors of the viral DNA polymerase such as ganciclovir (GCV), valganciclovir (VGCV), foscarnet (FOS) and cidofovir (CDV). They all have in common that they can induce drug-resistant or even cross-resistant HCMV variants and are associated with severe toxicity, which prevents long-term efficiency of therapy (Dropulic and Cohen, 2010). Recently, the U.S. Food and Drug Administration (FDA) approved Prevymis® (letermovir, LMV) tablets for the prophylaxis of HCMV infection in HCMV-seropositive recipients of allogeneic hematopoietic stem cell transplant (Bowman et al., 2017; Chemaly et al., 2014; Kropeit et al., 2017; Lischka et al., 2016). LMV exclusively targets a viral protein, the HCMV terminase, so that drug resistance may also arise in this case (Chou, 2015; Goldner et al., 2014). These limitations create a need for novel antiviral drugs with activity against HCMV variants that are resistant to conventional drugs and those with an even broader range of efficacy. Since HCMV replication is a complex process regulated by a precisely coordinated interplay of numerous viral and cellular proteins, the exploitation of genetically stable host factors essential for HMCV replication could be a suitable strategy to improve the general problem of selecting drug-resistant viruses. Here, we describe an innovative approach with a novel small molecule, SC88941, targeting a set of cellular factors crucial for the efficiency of virus replication. Thus, SC88941 represents a highly interesting candidate for the development of a novel antiviral drug.
Section snippets
Antiviral compounds
The compounds SC88941, SC105889 and SC106455 were synthesized in the laboratory of 4SC AG/4SC Discovery GmbH as described in detail in the Supplementary material. Antiviral reference drugs were obtained from the following sources: artesunate (ART; Saokim Ltd., Hanoi, Vietnam), ganciclovir (GCV; Sigma Aldrich), cidofovir (CDV; Pharmacia & Upjohn S.A., Luxembourg), letermovir (LMV; Cayman-Biomol), staurosporine (STP), roscovitine and Gö6976 (all Calbiochem). Stock aliquots were prepared in DMSO
Synthesis and chemical properties of SC88941 and related compounds
Compounds of the class pyrrolopyridines, in contrast to previously published pyrrolopyrimidines (Turk et al., 1987; Jacobson et al., 1999), have not been used in antiherpesviral research so far. In this study, we aimed at analyzing a series of pyrrolopyridines in their potency to inhibit HCMV replication in vitro. The compound SC88941 and derivatives, such as SC105889 and SC106455, were synthesized according to the procedures described in detail (Supplemental material; Schemes S1 and S2). All
Discussion
In this study we describe the antiviral activity of SC88941, a novel experimental drug candidate based on a pyrrolopyridine backbone. Previously, nucleosides and non-nucleosides of the pyrrolopyrimidine class that comprise a similar backbone have been extensively studied and revealed an anti-HCMV activity mediated by different mechanisms (Evers et al., 2004; Jacobson et al., 1999; Renau et al., 1992, 1996; Turk et al., 1987). In contrast to pyrrolopyrimidines, pyrrolopyridin derivatives have
Conflicts of interest
The authors have declared that no competing interests exist.
Acknowledgements
We like to thank Thomas Stamminger (Virology, Univ. Ulm, Germany), Svetlana B. Tsogoeva (Organic Chemistry, FAU Erlangen-Nürnberg, Germany), László Örfi (Vichem Chemie Ltd. and Semmelweis Univ. Budapest, Hungary) and Sunwen Chou (Virology, Univ. Portland, OR, USA) for support of this project and long-term cooperation in antiviral research. Many thanks also to Sabrina Wagner, Regina Müller and Isabel Zeitträger for excellent technical assistance. The study was supported by grants from the
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- 1
These authors contributed equally to the study.
- 2
Current address: BioNTech Small Molecules GmbH, Am Klopferspitz 19a, 82152 Planegg-Martinsried, Germany.