Structure-Driven Discovery of α,γ-Diketoacid Inhibitors Against UL89 Herpesvirus Terminase

Salvatore Bongarzone; Marta Nadal; Zuzanna Kaczmarska; Cristina Machón; Mercedes Álvarez; Fernando Albericio; Miquel Coll

doi:10.1021/acsomega.8b01472

Structure-Driven Discovery of α,γ-Diketoacid Inhibitors Against UL89 Herpesvirus Terminase

ACS Omega. 2018 Aug 1;3(8):8497-8505. doi: 10.1021/acsomega.8b01472. eCollection 2018 Aug 31.

Authors

Salvatore Bongarzone^{1

2}, Marta Nadal^{1

2}, Zuzanna Kaczmarska^{1

2}, Cristina Machón^{1

2}, Mercedes Álvarez^{1

3

4}, Fernando Albericio^{1

3

5}, Miquel Coll^{1

2}

Affiliations

¹ Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
² Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona Science Park, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
³ CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, 08028 Barcelona, Spain.
⁴ Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, 08028 Barcelona, Spain.
⁵ Department of Organic Chemistry, University of Barcelona, Martí i Franquès 1, 08028 Barcelona, Spain.

Abstract

Human cytomegalovirus (HCMV) is an opportunistic pathogen causing a variety of severe viral infections, including irreversible congenital disabilities. Nowadays, HCMV infection is treated by inhibiting the viral DNA polymerase. However, DNA polymerase inhibitors have several drawbacks. An alternative strategy is to use compounds against the packaging machinery or terminase complex, which is essential for viral replication. Our discovery that raltegravir (1), a human immunodeficiency virus drug, inhibits the nuclease function of UL89, one of the protein subunits of the complex, prompted us to further develop terminase inhibitors. On the basis of the structure of 1, a library of diketoacid (α,γ-DKA and β,δ-DKA) derivatives were synthesized and tested for UL89-C nuclease activity. The mode of action of α,γ-DKA derivatives on the UL89 active site was elucidated by using X-ray crystallography, molecular docking, and in vitro experiments. Our studies identified α,γ-DKA derivative 14 able to inhibit UL89 in vitro in the low micromolar range, making 14 an optimal candidate for further development and virus-infected cell assay.