Various (North)-methanocarba adenosine derivatives, containing rigid bicyclo[3.1.0]hexane ribose substitution, were screened for activity against representative viruses, and inhibition was observed after treatment of Enterovirus A71 with a 2-chloro- N 6-1-cyclopropyl-2-methylpropan-1-yl derivative ( 17 ). µM activity was also seen when testing 17 against other enteroviruses in the Picornaviridae family. Based on this hit, structural congeners of 17 , containing other N 6-alkyl groups and 5′ modifications, were synthesized and tested. The structure activity relationship is relatively narrow, with most modifications of the adenine or the methanocarba ring reducing or abolishing the inhibitory potency. 4′-Truncated 31 (MRS5474), 4′-fluoromethyl 48 (MRS7704) and 4′-chloromethyl 49 nucleosides displayed EC50 ~3–4 µM, and 31 and 48 achieved SI ≥10. However, methanocarba analogues of ribavirin and N 6-benzyladenosine, shown previously to have anti-EV-A71 activity, were inactive. Thus, we identified methanocarba nucleosides as a new scaffold for enterovirus inhibition with a narrow structure activity relationship and no similarity to previously published anti-enteroviral nucleosides.