Methylene bisphosphonates as the inhibitors of HIV RT phosphorolytic activity

• Published in: Biochimie Vol. 127; pp. 153 - 162
• Main Authors: Yanvarev, D.V., Korovina, A.N., Usanov, N.N., Khomich, O.A., Vepsäläinen, J., Puljula, E., Kukhanova, M.K., Kochetkov, S.N.
• Format: Journal Article
• Language: English
• Published: France Elsevier B.V 01-08-2016
• Subjects: Adenosine Triphosphate - metabolism; Bisphosphonates; Diphosphonates - pharmacology; DNA-Directed DNA Polymerase - metabolism; Excision; HIV; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV Reverse Transcriptase - metabolism; HIV-1 - enzymology; Magnesium - metabolism; Models, Molecular; Mutation; Nucleic Acid Conformation; Phosphorylation - drug effects; Protein Conformation; Pyrophosphorolysis; Resistance; Reverse transcriptase; RNA, Viral - chemistry; RNA, Viral - metabolism; SAR; Structure-Activity Relationship; TAM; TAM; RT; Reverse transcriptase; Excision; SAR; NNRTI; PPi; dNTP; Bisphosphonates; BP; Resistance; HIV; Pyrophosphorolysis; VDPA; AZT; NRTI
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2016.05.012

The structure-function analysis of 36 methylenebisphosphonates (BPs) as inhibitors of the phosphorolytic activity of native and drug-resistant forms of HIV-1 reverse transcriptase (RT) was performed. It was shown that with the increase of the inhibitory potential of BPs towards the phosphorolytic activity raises their ability to inhibit the RT-catalyzed DNA elongation. Herein, we report the impact of the thymidine analog mutations (TAM) on the activity of bisphosphonates, as well as some structural features of the BPs, allowing them to maintain the inhibitory activity on the enzyme resistant to nucleoside analog therapy. We estimated the Mg2+-coordinating group structure, the linker and the aromatic pharmacophore influence on the inhibitory potential of the BPs. Based on the 31 BPs SAR, several BPs with improved inhibitory properties were designed and synthesized.
•Described properties of 36 bisphosphonates as inhibitors of HIV RT.•SAR studies for 31 bisphosphonates.•Rational design and synthesis of five inhibitors based on SAR.•The impact of the thymidine analog mutations (TAM) on the activity of the inhibitors.•Mg2+-coordinating group determines inhibitory potential and sensitivity to TAM.