This paper describes a simple, microscale method for generating and evaluating libraries of derivatives of poly(acrylic acid) (pAA) that present mixtures of side chains that influence their biological activity. The method is based on the one-step conversion of poly(acrylic anhydride) (pAAn) to linear polymers presenting multiple units of R on side chains, pAA(R) : the polymers are obtained by ultrasonication of a suspension of pAAn and aqueous RNH2 contained in a 250-mu L well of a microtiter plate. Using this method, derivatives of pAA having N-acetylneuraminic acid (NeuAc-L-NH2) as a side chain, pAA(NeuAc-L), were generated and assayed for ability to inhibit hemagglutination (HAI) of chicken erythrocytes by influenza virus A (X-31); the constant (KHAT) describing this inhibition is calculated on the basis of the concentration of NeuAc groups in solution, rather than the concentration of polymer molecules. Go-polymeric pAA(NeuAc-L-n; L-n=different linking groups) with a range of mole fractions of NeuAc-L-NH2 (chi(NeuAc-L)=0.02-0.11) exhibited HAI activities with K-i(HAI) values between 27 and 0.30 mu M. Using combinations of NeuAc-L-NH2 and one of 26 different primary amines RNH2, a variety of ter-polymeric pAA(NeuAc-L; R) (chi(Neu-Ac-L)similar to 0.05; chi(R) similar to 0.06) were also generated and assayed. Certain ter-polymers yielded values of K-i(HAI) that were lower by a factor of similar to 10(4) than that of the parent co-polymeric pAA(NeuAc-L) : the most active inhibitor was pAA(NeuAc-L; L-3-(2’-naphthyl)alanine)) (K(i)(HAI)approximate to 0.05 mM). Typically, the incorporation of hydrophobic-especially aromatic-side chains enhanced activities. These polymers (pAA(NeuAc-L; R)) belong to a new class of polymeric, polyvalent sialosides that are potent inhibitors of the adsorption of influenza virus to erythrocytes. They were active with only low to moderate levels of incorporation of functional groups into the side chains : chi(NeuAc-L)similar to 0.05; chi(R) similar to 0.06.