Development of modified nucleosides that have supremely high anti-HIV activity and low toxicity and prevent the emergence of resistant HIV mutants

Abstract

An idea to use 4′-C-substituted-2′-deoxynucleoside derivatives was proposed based on a working hypothesis to solve the problems of existing acquired immune deficiency syndrome chemotherapy (highly active antiretroviral therapy). Subsequent studies have successfully proved the validity of the idea and resulted in the development of 2′-deoxy-4′-C-ethynyl-2-fluoroadenosine and 2′-deoxy-4′-C-ethynyl-2-chloroadenosine, nucleoside reverse transcriptase inhibitors, which have supremely high activity against all human immunodeficiency viruses including multidrug-resistant HIV and low toxicity.

The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase

“…In addition, as described, the present study showed that EFdA and related NRTIs with the 4′-ethynyl or 4′-cyano moiety showed very potent activity against HIV-1 M184V and HIV-1 EFdA R ; however, related compounds with other moieties such as the 4′-methyl moiety did not show any activity. The result was also consistent to the previous studies for other 4′-modified NRTIs (Kohgo et al, 1999; Ohrui et al, 2011). Taken together, this finding suggests that the structure of the 4′-moiety of NRTIs determines the activity of the NRTIs not only against HIV-1 or HBV but also against drug-resistant HIV-1 variants.…”

Design, Synthesis, and Biological Evaluation of EdAP, a 4′-Ethynyl-2′-Deoxyadenosine 5′-Monophosphate Analog, as a Potent Influenza a Inhibitor

“…The introduced phosphate ester could be cleaved in cells to generate phosphate monoester. EdA ( 2 ) was easily hydrolyzed by adenosine deaminase to generate the corresponding inactive inosine derivative [6,11,37]. However, EdAP, which has the same scaffold as EdA, except in the case of cyclosaligenyl phosphate ester, exhibited anti-influenza activity.…”

“…The inhibitors should work against several subtypes of influenza A viruses and be tolerated by a drug-resistant mutant because it is highly conserved in all influenza subtypes and is essential to the viral life cycle. We have previously reported on a highly potent antihuman immunodeficiency virus (HIV) nucleoside derivative called 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA, 1 , Figure 1) [5,6,7,8,9,10,11,12,13]. EFdA is an adenosine derivative armed with an ethynyl group at the 4′-position, which prevents the extension of a nucleotide at 3′-OH because of its steric hindrance by the 4′-substituent, providing features of a viral DNA chain terminator and a reverse transcriptase inhibitor [14,15,16,17,18].…”

Nucleosides and Nucleotides for the Treatment of Viral Diseases

“…Various fatty acid conjugates of AZT (13D), d4T (14A-D), and 3TC (15B-D and 16B and C) were prepared. 14,15 Several such derivatives have progressed, including the thymidine derivative BMS-986001 (festinavir, 18) and 2 0 -deoxy-4 0 -C-ethynyl-2-fluoroadenosine (EFdA, 19). Another approach investigated 1,3-diacylglycerol conjugates of AZT 5 0monophosphate in which the conjugate 17 demonstrated anti-HIV activity similar to the parent nucleoside AZT but suffered from chemical and enzymatic instability.…”

“…14,15 Several such derivatives have progressed, including the thymidine derivative BMS-986001 (festinavir, 18) and 2 0 -deoxy-4 0 -C-ethynyl-2-fluoroadenosine (EFdA, 19). 14 19 also showed activity against M184V and multidrug-resistant HIV-1 strains and had minimal effect on human mitochondrial DNA polymerase γ, with an EC 50 ¼ 10 μM, or human DNA polymerases α and β. It showed equivalent activity against wild-type HIV-1 and HIV-1 with K65R and Q151M RT mutations, but reduced potency against multidrug-resistant isolates.…”