Design, Synthesis, and Anti-RNA Virus Activity of 6′-Fluorinated-Aristeromycin Analogues

Abstract

The 6′-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell Sadenosyl-L-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6′position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N 6 -methyladenosine analogues 2a−e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a−c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6′,6′-Difluoroaristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6′-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.

The 2019–2020 novel coronavirus (severe acute respiratory syndrome coronavirus 2) pandemic: A joint american college of academic international medicine-world academic council of emergency medicine multidisciplinary COVID-19 working group consensus paper

“…Table 7 provides a focused outline of key investigational agents and major takeaway points. To date, agents considered for clinical investigation in the context of COVID-19 include protease inhibitors (e.g., lopinavir, ritonavir);[ 501 505 509 540 541 542 543 544 545 546 ] nucleoside analogs (e.g., favipiravir, galidesivir, penciclovir, remdesivir, ribavirin);[ 515 547 ] 6′-fluorinated aristeromycin analogs;[ 548 549 ] acyclovir fleximer analogs;[ 550 551 ] interferon;[ 38 39 486 510 520 521 522 523 524 552 553 554 555 ] antimalarials;[ 231 486 487 488 489 490 491 492 493 494 495 496 497 498 556 ] neuraminidase inhibitors (e.g., peramivir, oseltamivir, zanamivir);[ 39 557 558 ] corticosteroids and immunomodulators;[ 15 39 291 480 481 482 483 484 485 ] antilice agent ivermectin;[ 559 560 ] as well as a highly heterogeneous group of other potential treatments. [ 528 529 530 531 561 562 563 564…”

Polymers in the Medical Antiviral Front-Line

“…Polymers based on this group have been discussed by Jeong et al as general antiviral polymers, however, some have only limited effect on few types of viruses. The most efficient of these polymers is illustrated in Figure 16, as well as its antiviral test results [149]. In addition, 6 -Fluorinated-aristeromycin analogs were proposed as antiviral materials, owing to their effect on the RNA polymerase (RdRp) and the host cell s-adenosyl-l-homocysteine (SAH) hydrolase.…”

Computer-Aided Design, Synthesis, and Antiviral Evaluation of Novel Acrylamides as Potential Inhibitors of E3-E2-E1 Glycoproteins Complex from Chikungunya Virus

“…Furthermore, studies involving organic synthesis have led to the obtainment of potential hit compounds, with low micromolar ranges. Among these, thiazolidine/rhodanine [ 51 ], peptidomimetic [ 52 ], thienopyrrole [ 53 , 54 ], triazolopyrimidinone [ 31 ], and adenosine analogs [ 55 ] have demonstrated excellent results. Therefore, one of the most promising chemical classes found in the literature is represented by acylhydrazone derivatives (and also acrylamide analogs), which have exhibited high activities with low cytotoxicity [ 56 , 57 , 58 , 59 ].…”