Structure-Driven Discovery of alpha,gamma-Diketoacid Inhibitors Against UL89 Herpesvirus Terminase
Por:
Bongarzone, S, Nadal, M, Kaczmarska, Z, Machon, C, Alvarez, M, Albericio, F, Coll, M
Publicada:
1 ago 2018
Resumen:
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 (alpha,gamma-DKA and beta, delta-DKA) derivatives were synthesized and tested for UL89-C nuclease activity. The mode of action of alpha,gamma-DKA derivatives on the UL89 active site was elucidated by using X-ray crystallography, molecular docking, and in vitro experiments. Our studies identified alpha,gamma-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.
Filiaciones:
Bongarzone, S:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain
CSIC, IBMB, Mol Biol Inst Barcelona, Barcelona Sci Pk,Baldiri Reixac 10-12, E-08003 Barcelona, Spain
St Thomas Hosp, Div Imaging Sci & Biomed Engn, Kings Coll London, Kings Hlth Partners, London SE1 7EH, England
Nadal, M:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain
CSIC, IBMB, Mol Biol Inst Barcelona, Barcelona Sci Pk,Baldiri Reixac 10-12, E-08003 Barcelona, Spain
Biomed Res Inst St Pau IIB St Pau, Mol Bases Dis, Barcelona 08025, Spain
Kaczmarska, Z:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain
CSIC, IBMB, Mol Biol Inst Barcelona, Barcelona Sci Pk,Baldiri Reixac 10-12, E-08003 Barcelona, Spain
Int Inst Mol & Cell Biol, 4 Ksiecia Trojdena, PL-02109 Warsaw, Poland
Machon, C:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain
CSIC, IBMB, Mol Biol Inst Barcelona, Barcelona Sci Pk,Baldiri Reixac 10-12, E-08003 Barcelona, Spain
Alvarez, M:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain
CIBER, Networking Ctr Bioengn Biomat & Nanomed, BBN, Barcelona Sci Pk, Barcelona, Spain
Univ Barcelona, Fac Pharm, Lab Organ Chem, E-08028 Barcelona, Spain
Albericio, F:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain
CIBER, Networking Ctr Bioengn Biomat & Nanomed, BBN, Barcelona Sci Pk, Barcelona, Spain
Univ Barcelona, Dept Organ Chem, Marti & Franques 1, E-08028 Barcelona, Spain
Coll, M:
Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Baldiri Reixac 10-12, Barcelona 08028, Spain
CSIC, IBMB, Mol Biol Inst Barcelona, Barcelona Sci Pk,Baldiri Reixac 10-12, E-08003 Barcelona, Spain
Green Published, gold
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