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Aberrant WNT pathway activation, leading to nuclear accumulation of β‐catenin, is a key oncogenic driver event. Mutations in the tumor suppressor gene APC lead to impaired proteasomal degradation of β‐catenin and subsequent nuclear translocation. Restoring cellular degradation of β‐catenin represents a potential therapeutic strategy. Here, we report the fragment‐based discovery of a small molecule binder to β‐catenin, including the structural elucidation of the binding mode by X‐ray crystallography. The difficulty in drugging β‐catenin was confirmed as the primary screening campaigns identified only few and very weak hits. Iterative virtual and NMR screening techniques were required to discover a compound with sufficient potency to be able to obtain an X‐ray co‐crystal structure. The binding site is located between armadillo repeats two and three, adjacent to the BCL9 and TCF4 binding sites. Genetic studies show that it is unlikely to be useful for the development of protein–protein interaction inhibitors but structural information and established assays provide a solid basis for a prospective optimization towards β‐catenin proteolysis targeting chimeras (PROTACs) as alternative modality., Targeting the armadillo repeat: We report the fragment‐based discovery of a small‐molecule binder to the key cancer target β‐catenin. Iterative virtual screening and ligand‐based NMR techniques enabled hit optimization in absence of structural information. The co‐crystal structure of a derivative in complex with a short β‐catenin variant revealed a novel small‐molecule binding site between armadillo repeats two and three.

A library of 24 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10{1,2; 1–12} was prepared by a parallel solution-phase approach. The synthesis comprises a five-step transformation of itaconic acid (11) into 1-methyl and 1-phenyl substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylic acids 17{1,2} followed by parallel amidation of 17{1,2} with a series of 12 aliphatic amines 18{1–12} to afford the corresponding carboxamides 10 in good overall yields and in 80–100% purity.

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+.

Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ7-hexahydropyrazolo[1,5-a]pyridin-8-ium-1-ide, were prepared in seven steps from the respective commercially available δ-keto acids. The addition of Grignard reagents followed by N-alkylation at position 1 afforded the 1,7,7-trisubstituted hexahydropyrazolo[1,5-a]pyridin-2(1H)-ones, whereas 1,3-dipolar cycloadditions of these dipoles to typical acetylenic and olefinic dipolarophiles gave 4a-substituted 2a,2a1-diazacyclopenta[cd]indene derivatives as the first representatives of a novel heterocyclic system. Regio- and stereoselectivity as well as the mechanism of these [3 + 2]-cycloadditions were evaluated using computational and experimental methods. The data obtained were in agreement with the polar concerted cycloaddition mechanism via the energetically favorable syn/endo-transition states.

1,5-Disubstituted-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-7-carboxamides functionalized at positions 1, 5, and 7 were prepared in six straightforward steps from cheap, commercially available dialkyl acetone-1,3-dicarboxylate. Due to the instability of methyl 1-benzyl-substituted pyrazolo[4,3-c]pyridine-7-carboxylates under basic hydrolytic conditions (LiOH/H2O), a detour via the corresponding benzyl esters was introduced to deliver the final 1-benzyl-substituted-bicyclic carboxamides in seven steps. The designed synthetic route is suitable for the construction of a larger library of compounds. All the key compounds have been characterized by NMR spectroscopic techniques and X-ray analysis.

Two variants of the synthesis of 6-alkyl-7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-3-carboxamides have been developed. The first pathway comprises nine steps starting with the introduction of the 6-alkyl group (R1) via addition of a primary alkylamine to methyl acrylate followed by a seven-step transformation into the 6-benzyl-7-oxo-4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidine-3-carboxylic acid, which is then amidated into title compounds. The other variation is based on an analogous four-step transformation of Boc-β-alanine into a 6-unsubstituted benzyl ester as the key intermediate. The 6-alkyl group (R1) is then introduced by N-alkylation with alkyl halides, followed by O-debenzylation to give the carboxylic acids, and amidation. A library of 18 title carboxamides was prepared in very good yields.

The synthesis of 7-substituted pyrazolo[1,5-a]pyrimidine-3-carboxamides was studied. First, methyl 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (5) was prepared in three steps from methyl 5-amino-1H-pyrazole-4-carboxylate (3). Treatment of 5 with POCl3 gave the highly reactive 7-chloro derivative 10, which was reacted with amines, benzyl alcohol, and phenylboronic acid in the presence of Pd-catalyst to give the corresponding 7-substituted derivatives 11. Hydrolysis of the esters 5 and 11 followed by amidation gave the corresponding carboxamides 16a–h and 15. Regioselectivity of N-alkylation of 7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylic acid derivatives 5 and 16 was tunable by the carboxy function. Alkylation of the secondary amides 16a–f furnished the 1-alkyl derivatives 17a–f, whereas the ester 5 and the tertiary amides 16g,h gave the 4-alkyl derivatives 14a–d and 16m,n, selectively.

A novel simple five-step synthesis of 1,6-disubstituted tetrahydropyrazolo[1,5- c ]pyrimidine-2,7(1 H ,3 H )-diones has been developed. The synthetic protocol starts with ‘ring switching’ transformation of commercially available 5,6-dihydro-2 H -pyran-2-one into the 5-(2-hydroxyethyl)pyrazolidin-3-one, followed by addition of the latter to isocyanates, Appel bromination, cyclization, and N(1)-alkylation with alkyl halides to give the title compounds. In comparison to a 12-step synthesis reported recently, the present method is clearly superior with respect to the number of synthetic steps and versatility of substituents at position 6.

A simple and practical four-step protocol for the parallel synthesis of 7-heteroaryl-pyrazolo[1,5- $$a$$ ]pyrimidine-3-carboxamides was developed. The synthesis starts with transformation of commercially available 2-acetylpyridine and acetylpyrazine with $$N,$$ $$N$$ -dimethylformamide dimethylacetal into the corresponding $$(E)$$ -3-(dimethylamino)-1-(heteroaryl)prop-2-en-1-ones followed by cyclisation with methyl 5-amino-1 $$H$$ -pyrazole-4-carboxylate to give methyl 7-heteroarylpyrazolo[1,5- $$a$$ ]pyrimidine-3-carboxylates. Hydrolysis of the ester group and subsequent amidation of the so formed carboxylic acids with 12 primary and secondary aliphatic amines furnished a library of 24 title compounds in good overall yields and purity.

2-Substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidin-4(3 H )-ones were synthesized in three steps from itaconic acid derivatives via cyclization with primary amines followed by Masamune-Claisen condensation, and cyclization of the newly formed β -keto esters with amidines. Preparation and/or isolation of β-keto esters with polar N -substituents failed, but the corresponding final products were obtained in a different way. 6-(1-(3-Hydroxypropyl)-5-oxopyrrolidin-3-yl)-2-phenylpyrimidin-4(3 H )-one was obtained by hydrogenolytic o-deprotection of its o -benzyl derivative. Depending on reaction conditions, further mesylation of 6-(1-(3-(benzyloxy)propyl)-5-oxopyrrolidin-3-yl)-2-phenylpyrimidin-4(3 H )-one followed by treatment with pyrrolidine gave either the monoaminated- or the diaminated product. The structures of novel compounds were determined by NMR.

A series of tetrahydropyrazolo[1,5- c ]pyrimidine-2,7(1 H ,3 H )-diones 3a – h as the first representatives of the so far unexplored saturated heterocyclic system have been synthesized, formally in 12 steps from methyl acrylate ( 4 ). The synthesis comprises a four-step preparation of methyl N -Cbz-5-alkylamino-3-oxopentanoates 9a–c , their three-step transformation into 5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a – c , three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 16b – h , followed by hydrogenolytic Cbz-deprotection and subsequent cyclization of the intermediate 1,4-diamine with CDI to furnish the title compounds 3 . Most of the synthetic steps were performed as a one-pot transformation.

Two cyclic azomethine imines, 7-methyl- and 7-phenyl-2-oxo-Δ

A simple five-step diversity-oriented synthesis of 1-substituted 4-aryl-6-oxo-1,6-dihydropyridine-3-carboxamides was developed. Treatment of dimethyl 2-((dimethylamino)methylidene)-3-oxopentanedioate with twenty primary amines gave 1-substituted methyl 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carboxylates. Transformation into the corresponding 4-tosyloxy and 4-chloro derivatives, followed by Suzuki-Miyaura arylations gave a series of eleven N-substituted methyl 4-aryl-6-oxo-1,6-dihydropyridine-3-carboxylates. Combinatorial screening was employed to establish suitable reaction conditions for Suzuki-Miyaura arylation of N-alkylpyridones. Hydrolysis of the esters followed by parallel solution-phase amidation of the corresponding carboxylic acids with primary and secondary amines furnished a library of seventeen final products.

A library of twelve N(4´)-substituted di-tert-butyl (2S,4E)-4-arylaminomethylidene-5-oxopyrrolidine-1,2-dicarboxylates 6/6´a - l were prepared in 47 - 90% yield by parallel acid-catalysed treatment of di-tert-butyl (2S,4E)-4-[(dimethylamino)methylidene]-5-oxopyrrolidine-1,2-dicarboxylate (4) with anilines 5a - j, ethyl glycinate (5k), and ethyl β -alaninate (3l). Acidolytic deprotection of compounds 6a - c, e - j afforded the corresponding (2S,4E)-4-arylaminomethylidene-5-oxopyrrolidine-2-carboxylic acids 7a - c, e - j in 39 - 99% yield. The configuration around the C=C double bond in the enaminones 6 and 7 was determined by NMR spectroscopy.

A seven-step synthesis of 1-substituted 5-(2-acylaminoethyl)-1H-pyrazole-4-carboxamides 20 as the pyrazole analogues of histamine was developed. The synthesis starts with a three-step preparation of N(1)-substituted methyl 5-(2-tert-butoxycarbonylaminoethyl)-1H-pyrazole-4-carboxylates 7 from commercially available Boc-β-alanine (1). Subsequent four-step transformation of the key-intermediates 7 into the final products 20 was performed following two complementary reaction sequences comprising acidolytic removal of the Boc group, hydrolysis of the COOMe group, amidations of the COOH group, and acylations of the NH2 group. The structures of pyrazole derivatives were determined by spectroscopic methods and by X-ray diffraction.

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a–k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l–o. Benzamides 7a–k and 7′l–o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a–k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l–o in good overall yields.

An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.

A novel simple five-step synthesis of 1,6-disubstituted tetrahydropyrazolo[1,5- c ]pyrimidine-2,7(1 H ,3 H )-diones has been developed. The synthetic protocol starts with ‘ring switching’ transformation of commercially available 5,6-dihydro-2 H -pyran-2-one into the 5-(2-hydroxyethyl)pyrazolidin-3-one, followed by addition of the latter to isocyanates, Appel bromination, cyclization, and N(1)-alkylation with alkyl halides to give the title compounds. In comparison to a 12-step synthesis reported recently, the present method is clearly superior with respect to the number of synthetic steps and versatility of substituents at position 6.

A series of tetrahydropyrazolo[1,5- c ]pyrimidine-2,7(1 H ,3 H )-diones 3a – h as the first representatives of the so far unexplored saturated heterocyclic system have been synthesized, formally in 12 steps from methyl acrylate ( 4 ). The synthesis comprises a four-step preparation of methyl N -Cbz-5-alkylamino-3-oxopentanoates 9a–c , their three-step transformation into 5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a – c , three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 16b – h , followed by hydrogenolytic Cbz-deprotection and subsequent cyclization of the intermediate 1,4-diamine with CDI to furnish the title compounds 3 . Most of the synthetic steps were performed as a one-pot transformation.

An ELISA assay is described for measuring the binding of influenza virus A-X31 to α-sialoside groups that are linked to biotin-labeled polyacrylamides. The efficacy of these polymers in inhibiting the adhesion of influenza virus to erythrocytes (as measured by a hemagglutination assay) was shown to be directly related to the binding affinity of the polymers for the viral surface: the differences in inhibitory efficacy among the polymeric inhibitors and monomeric α-methyl sialoside, among fractions of a polymeric, polyvalent inhibitor with narrow molecular weight ranges, and among polymeric inhibitors prepared by copolymerization or modification of a preformed polymer chain, all correlated with differences in the affinity of the inhibitors for the surface of the virus. The polymeric inhibitors studied had affinities for the viral surface that ranged between 103 and >106 greater than α-methyl sialoside, on the basis of total sialic acid groups in solution. The role of steric stabilization in the mechanism ...

A degradation product 2 of muamvatin has been synthesized starting from the stereodefined building blocks 7 and 9. This synthesis allowed assignment of the absolute configuration of muamvatin as well as of the relative configuration at all stereocenters except for C-11. The latter configuration is proposed on the basis of the 1H-NMR data of natural muamvatin. Attempts have been made to clarify the configuration at C-11 of muamvatin by synthesis starting from the aldehyde 9 and the ketones 28.

A protected hydroxy triketone 22 has been generated by direct Swern oxidation of a δ-trimethylsilyloxy alcohol 11, avoiding the formation of a δ-hydroxy ketone as an intermediate. Conditions have been worked out, which allow the deprotection of a tert-butyldimethylsilyl group and the spontaneous tricyclization of the resulting hydroxy triketone 4 to an acid-sensitive hydroxytrioxaadamantane 5.

The stereotriad D has been the most elusive one to obtain in the course of the synthesis of polyketide derived natural products. Many research groups involved in such endeavours have contributed original approaches to this seemingly simple structural unit. The most popular approach is to generate a building block that contains all the stereocenters of the triad D. The molecular skeleton may then be extended from such a buil- ding block in two directions. We describe here our own route to such building blocks, being based on an enantioselective crotylboration of methacrolein followed by a diastereoselective hydroboration reaction

Both epimers of the aldehyde 2 , a degradation product of muamvatin, have been synthesized in a streodefined manner. This allowed us to assign the relative and absolute configuration to muamvatin as shown in 19 . Key to this synthesis was a novel chiral building block 10 , representing the stereotriad D.

A degradation product 2 of muamvatin has been synthesized starting from the stereodefined building blocks 7 and 9. This synthesis allowed assignment of the absolute configuration of muamvatin as well as of the relative configuration at all stereocenters except for C-11. The latter configuration is proposed on the basis of the 1H-NMR data of natural muamvatin. Attempts have been made to clarify the configuration at C-11 of muamvatin by synthesis starting from the aldehyde 9 and the ketones 28.

A highly selective series of bisbenzamide inhibitors of Rho-associated coiled-coil forming protein kinase (ROCK) and a related ureidobenzamide series, both identified by high throughput screening (HTS), are described. Details of the hit validation and lead generation process, including structure-activity relationship (SAR) studies, a selectivity assessment, target-independent profiling (TIP) results, and an analysis of functional activity using a rat aortic ring assay are discussed.

Two variations of enaminone-based parallel solution-phase synthesis of 1-substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols 8 and their NH-tautomers 8′ were developed. The synthetic strategy comprises a two step preparation of the N-protected α-enamino lactams 3a and 3b from 2-pyrrolidinone (1), “ring switching” transformation of 3a,b with monosubstituted hydrazines 4a−u, and acidolytic removal of the N-protecting group. In order to ensure a clean and fast conversion, reactions of Cbz-enaminone 3a with hydrazines 4a−k were carried out under microwave irradiation to afford the “ring-switched” intermediates 7a−k. Deprotection of 7a−k with HBr−AcOH at 50 °C gave a library of 11 analytically pure 4-(2-aminoethyl)-1H-pyrazol-5-ols (di)hydrobromides 8/8’a−k in 16−75% yields over two steps. The other reagent, Boc-enaminone 3b, was more reactive and ring switching transformations with hydrazines 4b,d,k proceeded smoothly and cleanly under conventional heating. Finally, a parallel one-pot transformation of the Boc-enam...

The total synthesis of the denticulatins 1 is described. Key feature is the efficient generation of the C-1-to-C-9 building block 37 by three consecutive stereoselective carbon - carbon bond-forming steps using chiral allylboronates. The C-10-to-C-17 building block was obtained by kinetic Sharpless resolution of an allylic alcohol followed by an Ireland-Claisen rearrangement.

Two variations of enaminone-based parallel solution-phase synthesis of 1-substituted 4-(2-aminoethyl)-1 H-pyrazol-5-ols 8 and their NH-tautomers 8' were developed. The synthetic strategy comprises a two step preparation of the N-protected alpha-enamino lactams 3a and 3b from 2-pyrrolidinone (1), "ring switching" transformation of 3a, b with monosubstituted hydrazines 4a-u, and acidolytic removal of the N-protecting group. In order to ensure a clean and fast conversion, reactions of Cbz-enaminone 3a with hydrazines 4a-k were carried out under microwave irradiation to afford the "ring-switched" intermediates 7a-k. Deprotection of 7a-k with HBr-AcOH at 50 degrees C gave a library of 11 analytically pure 4-(2-aminoethyl)-1 H-pyrazol-5-ols (di)hydrobromides 8/ 8'a-k in 16-75% yields over two steps. The other reagent, Boc-enaminone 3b, was more reactive and ring switching transformations with hydrazines 4b, d, k proceeded smoothly and cleanly under conventional heating. Finally, a parallel one-pot transformation of the Boc-enaminone 3b with hydrazines 4a-u followed by subsequent deprotection of the intermediates 9a-u with HCl-EtOAc furnished a library of 21 analytically pure 4-(2-aminoethyl)-1 H-pyrazol-5-ols (di)hydrochlorides 8/ 8'a-u in 40-100% yields.

A simple four-step synthesis of 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8 (or their 1H-pyrazol-3(2H)-one tautomers 8′) as the pyrazole analogues of histamine was developed. First, enamino lactam 3 was prepared as the key intermediate in two steps from 2-pyrrolidinone (1). Next, acid-catalysed ‘ring switching’ transformations of 3 with monosubstituted hydrazines 4 gave N-[(1-substituted 5-hydroxy-1H-pyrazol-4-yl)ethyl]benzamides 7a–k and N-[2-(2-heteroaryl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)ethyl]benzamides 7′l–o. Benzamides 7a–k and 7′l–o were finally hydrolysed by heating in 6 M hydrochloric acid to furnish 1-substituted 4-(2-aminoethyl)-5-hydroxy-1H-pyrazoles 8a–k and 4-(2-aminoethyl)-2-heteroaryl-1H-pyrazol-3(2H)-ones 8′l–o in good overall yields.

Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides.

A variety of (tetrahydrofuran-2-yl)acetates have been prepared based on hydrogenation and subsequent nucleophilic substitutions of 2-alkylidene-5-(hydroxymethyl)tetrahydrofurans. The latter are readily available by cyclization of 1,3-dicarbonyl dianions (“free dianions”) with epibromohydrin. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Highly effective sialic acid-containing inhibitors of influenza virus X-31 were synthesized using poly[N-(acryoyloxy)succinimide] (pNAS), a polymer preactivated by incorporation of active ester groups. Polymers containing two and three different components were prepared by sequential reaction of pNAS with two and three amines, respectively. This preparation of co- and terpolymers was synthetically more efficient than methods involving copolymerization of different monomers and gave polymers that were more easily compared than those generated by copolymerization. Polymers in this study (prepared from a single batch of pNAS) had a constant degree of polymerization (DP approximately 2000) and probably had a distribution of components that was more random than analogous polymers prepared by copolymerization. Use of C-glycosides of sialic acid made it possible to investigate inhibition by different polymers at temperatures ranging from 4 to 36 degrees C without artifacts due to the hydrolytic action of neuraminidase. The inhibitors were, in general, more effective at 36 degrees C than at 4 degrees C. The hemagglutination (HAI) assay was used to measure the value of the inhibition constant KHAIi each polymer. The value of KHAIi for the two-component polymer containing 20% sialic acid on a polyacrylamide backbone at 4 degrees C was 4 nM (in terms of the sialic acid moieties present in solution) and was approximately 50-fold more effective than the best inhibitors previously described and 25-fold more effective than the best naturally occurring inhibitor. The most effective inhibitor synthesized in this work contained 10% benzyl amine and 20% sialic acid on a polyacrylamide backbone, and its value of KHAIi was 600 pM at 36 degrees C. Approximately 100 polymers that differed in one or two components were assayed to distinguish between two limiting mechanisms for inhibition of the interaction between the surfaces of virus and erythrocytes: high-affinity binding through polyvalency, and steric stabilization. The results suggest that both mechanisms play an important role. The system comprising polyvalent inhibitors of agglutination of erythrocytes by influenza provides a system that may be useful as a model for inhibitors of other pathogen-host interactions, a large number of which are themselves polyvalent.