As shown in Table , both G5-and G13-psDiMan50% and 100% potently blocked cell surface DC-SIGN-promoted cell entry of EBOVpp. Their EC50 values were determined as 0.43 ± 0.17, 0.06 ± 0.03, 0.49 ± 0.13 and 0.18 ± 0.04 nM, respectively. Such impressively low EC50 values place them among Fig. . Normalized infection (after background correction of the control particle encoding no EBOV-GP gene) vs. concentration plot for G5-psDiMan (A) or G13-psDiMan (B) against DC-SIGN augmented, EBOV-GP driven entry into HEK293 cells fitted by Eq. 6. The fitting parameters were provided in Table . the most potent glycoconjugate inhibitors against DC-SIGNaugmented cell entry of EBOVpp. Moreover, a higher surface psDiMan content (e.g., Gx-psDiMan50% vs. Gx-psDiMan 100%) was found to increase the antiviral potency of both G5-and G13-psDiMan. These results broadly agree with their relative DC-SIGN binding affinities measured in solution by GNP based fluorescence quenching. Interestingly, both G5-psDiMan50% and 100% displayed negative inhibition cooperativity (n = ~0.5) while their G13 counterparts appeared to exhibit no or even positive cooperativity (n ≥ 1, after considering their relatively large fitting errors). Thus, a lower EC50 value for G5-psDiMan100% compared to that G13-psDiMan100% (e.g., 0.06± 0.03 vs. 0.18 ± 0.04 nM) does not necessarily mean that the former is a more effective antiviral than the latter. In fact, 3 nM G13-psDiMan100% completely blocked DC-SIGN-promoted EBOVpp cell entry (luciferase activity ≤ background signal of the control particle encoding no EBOV-GP gene), while its G5-counterpart only blocked ~80% of viral entry under the same concentration. The same trend was also observed for G5-and G13-psDiMan50%. This result highlighted the importance of "n" in determining the efficiency of antivirals: where both EC50 and "n" values much be considered together to obtain the true efficacy of antivirals. Further, it indicates that a large scaffold size is beneficial to antiviral properties of glycoconjugates based entry inhibitors. Interestingly, the antiviral property of G5-psDiMan is different from that of G5-DiMan (G5 coated with LA-EG2-EG2-DiMan, a natural DiMan ligand for DC-SIGN with the same overall EG linker length). The former inhibition displayed negative cooperativity (n = ~0.5) while the latter displayed non cooperativity (n = 1). Such differences are likely due to the different binding motifs between DiMan and psDiMan in binding to DC-SIGN CRDs. Crystal structures of psDiMan-DC-SIGN CRD complex revealed that psDiMan uses specific binding to the primary Ca 2+ site via its mannose residue and the cyclohexane framework of the modified mannose form multiple contacts with Val351. The restricted binding mode for psDiMan thus may require it to be presented at a specific orientation in order to maximize its binding contacts with DC-SIGN CRD. Whereas DiMan can coordinate the Ca 2+ site with both Man residues, resulting in multiple bind-ing modes which makes it more adaptable to CRD orientation. Since each LA based dithiol ligand forms 2 Au-S bonds on the GNP surface with an estimated total bonding enthalpy of ~90 kcal.mol , matching that of a typical single C-C covalent bond. As a result, the psDiMan ligands on the GNP surface should not be mobile, apart from the flexibility offered by the EG4 linker. Here, the EG4 linker may not be able to provide enough flexibility to fully compensate the psDiMan orientation on curved GNP surfaces, allowing us to observe the different viral inhibition properties between G5-psDiMan and G5-DiMan.