A family of 3′-functionalized thymidines carrying XCH2COOH (X=O, NH, S, SO2) groups has been designed as inhibitors of RNase A. This is because it is possible to manipulate the overall acidity of this new class of nucleic ‘acids’ by changing X from oxygen to the SO2 group in the series. It is also expected that the acyclic nature of the XCH2COOH group would provide enough flexibility to the –COOH group to have maximum interactions with the catalytic subsite P1 of RNase A. As the –SO2CH2COOH substituted derivative showed better potency partially because of the increased acidity of the –COOH group, the inhibitory properties of both 5′-substituted and 3′,5′-disubstituted sulfone acetic acid modified thymidines were investigated. Two –SO2CH2COOH groups were incorporated with the expectation of targeting two phosphate binding sites simultaneously. Thus, 3′,5′-dideoxy-3′,5′-bis-S-[(carboxymethyl)sulfonyl]thymidine emerged as the best inhibitor in this series with a Ki value of 25±2μM.