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Small-molecule fibroblast growth factor receptor (FGFR) inhibitors have emerged as a promising antitumor therapy. Herein, by further optimizing the lead compound 1under the guidance of molecular docking, we obtained a series of novel covalent FGFR inhibitors. After careful structure–activity relationship analysis, several compounds were identified to exhibit strong FGFR inhibitory activity and relatively better physicochemical and pharmacokinetic properties compared with those of 1. Among them, 2epotently and selectively inhibited the kinase activity of FGFR1–3 wildtype and high-incidence FGFR2-N549H/K-resistant mutant kinase. Furthermore, it suppressed cellular FGFR signaling, exhibiting considerable antiproliferative activity in FGFR-aberrant cancer cell lines. In addition, the oral administration of 2ein the FGFR1-amplified H1581, FGFR2-amplified NCI-H716, and SNU-16 tumor xenograft models demonstrated potent antitumor efficacy, inducing tumor stasis or even tumor regression.

The histone lysine methyltransferase NSD2 is overexpressed, translocated, or mutated in multiple types of cancers and has emerged as an attractive therapeutic target. However, the development of small-molecule NSD2 inhibitors is still in its infancy, and selective and efficacious NSD2 inhibitors are highly desirable. Here, in view of the structural novelty of the reported NSD2 inhibitor DA3003-1, we conducted a comprehensive structural optimization based on the quinoline-5,8-dione scaffold. Compound 15awas identified possessing both high NSD2 inhibitory activity and potent anti-proliferative effects in the cell. Meanwhile, compound 15ahas an excellent pharmacokinetic profile with high oral bioavailability. Further, this compound was found to display significant antitumor efficacy with desirable safety profile in the multiple myeloma xenograft mice models, thus warranting it as a promising candidate for further investigation.

Physalis minimais a medicinal and edible plant in China. In this study, 22 new withaphysalins, including a novel 1(10 → 6)abeo-14β-hydroxy one (1) and other 15 unusual 14β-hydroxy ones (3–4, 6–17, 19), were isolated from the whole herbs of P. minimatogether with two known analogues (23–24). Their structures were established by extensive analysis of high-resolution electrospray ionization mass spectrometry, IR, and 1D and 2D NMR spectroscopic data. Their absolute configurations were determined by electronic circular dichroism (ECD) spectra and single-crystal X-ray crystallographic analyses, together with DFT NMR calculations. All isolated compounds were evaluated for their anti-inflammatory activity via measuring the colorimetric reporter of the secreted embryonic alkaline phosphatase gene driven by an IFN-β minimal promoter fused to five copies of the NF-κB consensus transcriptional response element and three copies of the c-Rel binding site in LPS-stimulated human THP1-Dual cells. Compounds 2, 5, 6, 9, 10, 11, and 20showed significant anti-inflammatory effects with IC50values in the range of 3.01–13.39 μM. Among them, compounds 2and 10showed better anti-inflammatory effects to inhibit the secretion of IL-6, IL-1β, and TNF-α in LPS-stimulated THP1-Dual cells.

Background:Cognitive impairment, increasingly recognized as a major social burden, is commonly found in chronic kidney disease (CKD) patients. Summary:Vascular damage, uremic toxicity, oxidative stress, and peripheral/central inflammation induced by CKD might be involved in brain lesions and ultimately result in cognitive decline. Uncovering the pathophysiology of CKD-associated cognitive impairment is important for early diagnosis and prevention, which undoubtedly prompts innovative pharmacological treatments. Key Messages:Here, we sequentially review the current understanding and advances in the epidemiology, risk factors, and pathological mechanisms of cognitive impairment in CKD. Furthermore, we summarize the currently available therapeutic strategies for cognitive impairment in CKD.

It remains a big challenge to develop HDAC inhibitors effective for solid tumors. Previous studies have suggested that the feedback activation of JAK-STAT3 pathway represents a key mechanism leading to resistance to HDAC inhibitors in breast cancer, suggesting the therapeutic promise of JAK/HDAC dual inhibitors. In this work, we discovered a series of pyrrolo[2,3-d]pyrimidine-based derivatives as potent JAK and HDAC dual inhibitors. Especially, compounds 15dand 15hpotently inhibited JAK1/2/3 and HDAC1/6 and displayed antiproliferative and proapoptotic activities in triple-negative breast cancer cell lines. Besides, compounds 15dand 15halso diminished the activation of LIFR-JAK-STAT signaling triggered by tumor-associated fibroblasts, which suggests that these compounds could potentially overcome the drug resistance caused by the tumor microenvironment. More importantly, compound 15deffectively inhibited the tumor growth in MDA-MB-231 xenograft tumor model. Overall, this work provides valuable leads and novel antitumor mechanisms for the treatment of the SAHA-resistant triple-negative breast cancers.

CARM1 is a protein arginine methyltransferase and acts as a transcriptional coactivator regulating multiple biological processes. Aberrant expression of CARM1 has been related to the progression of multiple types of cancers, and therefore CARM1 was considered as a promising drug target. In the present work, we report the structure-based discovery of a series of N1-(3-(pyrimidin-2-yl)benzyl)ethane-1,2-diamines as potent CARM1 inhibitors, in which compound 43displays high potency and selectivity. With the advantage of excellent tissue distribution, compound 43demonstrated good in vivo efficacy for solid tumors. Furthermore, from the detailed immuno-oncology study with MC38 C57BL/6J xenograft model, we confirmed that this chemical probe 43has profound effects in tumor immunity, which paves the way for future studies on the modulation of arginine post-translational modification that could be utilized in solid tumor treatment and cancer immunotherapy.

Activation of the stimulator of interferon gene (STING) has emerged as an exciting immuno-oncology therapeutic strategy; however, the first-generation STING agonists, cyclic dinucleotide (CDN) analogues, have suffered from many disadvantages and failed in clinical trials. Therefore, non-CDN small-molecule STING agonists are urgently needed. In view of the unique structure of the high potency of dimeric amidobenzimidazole STING agonist 5, a structural elaboration was conducted by modifying several structural hotspots of this scaffold. Triazole 40was identified as a new potent STING activator, possessing EC50values of 0.24 and 39.51 μM for h- and m-STING, respectively. This compound has a slightly better pharmacokinetic profile and is >20-fold more aqueously soluble than 5. It activated the STING signaling dramatically by directly binding and stabilizing all h-STING isoforms and m-STING. In vivo, intermittent administration of 40was found to have significant antitumor efficacy with good tolerance in two mouse tumor models.

Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer’s disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

Alterations of fibroblast growth factor receptors (FGFRs) play key roles in numerous cancer progression and development, which makes FGFRs attractive targets in the cancer therapy. In the present study, based on a newly devised FGFR target-specific scoring function, a novel FGFR inhibitor hit was identified through virtual screening. Hit-to-lead optimization was then performed by integrating molecular docking and site-of-metabolism predictions with an array of in vitro evaluations and X-ray cocrystal structure determination, leading to a covalent FGFR inhibitor 15, which showed a highly selective and potent FGFR inhibition profile. Pharmacokinetic assessment, protein kinase profiling, and hERG inhibition evaluation were also conducted, and they confirmed the value of 15as a lead for further investigation. Overall, this study exemplifies the importance of the integrative use of computational methods and experimental techniques in drug discovery.

PRMT4 is a type I protein arginine methyltransferase and plays important roles in various cellular processes. Overexpression of PRMT4 has been found to be involved in several types of cancers. Selective and in vivo effective PRMT4 inhibitors are needed for demonstrating PRMT4 as a promising therapeutic target. On the basis of compound 6, a weak dual PRMT4/6 inhibitor, we constructed a tetrahydroisoquinoline scaffold through a cut-and-sew scaffold hopping strategy. The subsequent SAR optimization efforts employed structure-based approach led to the identification of a novel PRMT4 inhibitor 49. Compound 49exhibited prominently high potency and selectivity, moderate pharmacokinetic profiles, and good antitumor efficacy in acute myeloid leukemia xenograft model via oral administration, thus demonstrating this compound as a useful pharmacological tool for further target validation and drug development in cancer therapy.

Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-amino-pyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8mpossessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8mexhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8mexhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2V617Fmutation. Pharmacokinetic studies in mice showed that 8mpossessed good bioavailability after intraperitoneal administration. Finally, 8mshowed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.

Fibroblast growth factor receptors (FGFR1–4) are promising therapeutic targets in many cancers. With the resurgence of interest in irreversible inhibitors, efforts have been directed to the discovery of irreversible FGFR inhibitors. Currently, several selective irreversible inhibitors are being evaluated in clinical trials that could covalently target a conserved cysteine in the P-loop of FGFR. In this article, we used a structure-guided approach that is rationalized by a computer-aided simulation to discover the novel and irreversible pan-FGFR inhibitor, 9g, which provided superior FGFR in vitro activities and decent selectivity over VEGFR2 (vascular endothelia growth factor receptor 2). In in vivo studies, 9gdisplayed clear antitumor activities in NCI-H1581 and SNU-16 xenograft mice models. Additionally, the diluting method confirmed the irreversible binding of 9gto FGFR.

Sphingosine-1-phosphate (S1P) is a potent pleotropic bioactive lipid mediator involved in immune cell trafficking, cell survival, cell proliferation, cell migration, angiogenesis and many other cellular processes. S1P either activates S1P receptors (S1PR1-5) through “inside-out signaling” or acts directly on intracellular targets to regulate various cellular processes. In the past two decades, much progress has been made in exploring S1P signaling and its pathogenic roles in diseases as well as in developing modulators of S1P signaling, including S1P agonists, S1P antagonists and sphingosine kinase (SphK) inhibitors. Ceramide and S1P have been defined as reciprocal regulators of cell fate, and S1P signaling has been shown to be crucial for the pathogenesis of various diseases, including autoimmune diseases, inflammation and cancer; therefore, targeting S1P signaling may curtail the process of pathogenesis and serve as a potential therapeutic target for the treatment of these diseases. In this review, we describe recent advances in our understanding of S1P signaling in cancer development (particularly in inflammation- associated cancer) as well as in innate and adaptive immunity, and we also discuss modulators of S1P signaling in cancer treatment.

Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism remains unclear. This study considers the widely applied cytotoxic agent irinotecan (CPT-11) as a representative agent and demonstrates that treatment induces massive release of double-strand DNA from the intestine that accounts for the dose-limiting intestinal toxicity of the compound. Specifically, “self-DNA” released through exosome secretion enters the cytosol of innate immune cells and activates the AIM2 (absent in melanoma 2) inflammasome. This leads to mature IL-1ß and IL-18 secretion and induces intestinal mucositis and late-onset diarrhoea. Interestingly, abrogation of AIM2 signalling, either in AIM2-deficient mice or by a pharmacological inhibitor such as thalidomide, significantly reduces the incidence of drug-induced diarrhoea without affecting the anticancer efficacy of CPT-11. These findings provide mechanistic insights into how chemotherapy triggers innate immune responses causing intestinal toxicity, and reveal new chemotherapy regimens that maintain anti-tumour effects but circumvent the associated adverse inflammatory response.

In answering to the challenge of enzymatic unstability of Biopharmaceutics Classification System (BCS) class II drugs, an effective remote loading strategy was developed to successfully incorporate the drug–cyclodextrin (CD) complex into niosomes to modify the release and stability of a drug candidate, pseudolaric acid B (PAB). Judged by binding constants, and combined solubilization effects of pH and CD complexation on PAB at different pH, the complex internalization driven by a transmembrane pH gradient (from 2.0 to 7.4) and the dynamic shifting of PAB–CD complexation equilibrium at this gradient were introduced. The transfer of PAB–CD complex into the internal aqueous phase of niosomes at 60 °C was primarily verified by synchrotron radiation Fourier transform infrared spectroscopy. The remote loading samples behaved as retarded release at pH 5.8, 6.8, and 7.4, for which the stability of PAB in rat plasma was significantly enhanced (about 8.1-fold), in comparison with niosomes prepared by the passive and lipid bilayer loading of PAB. The drug–carrier interaction based release modeling was further fitted, and the convection rate constant (ks) and free energy difference between free and bound states (ΔG) indicated the strongest PAB–carrier interactions in remote loading niosomes. The remote loading strategy also reduced the CD–cholesterol interaction and provided better physical stability of the system. In conclusion, the remote loading of drug–CD complex into niosomes provides advantages to modify the release and enhance the stability of unstable BCS class II drug.

Variation of the cultivation conditions for Aspergillus glaucusled to the discovery of two novel spirocyclic aromatic polyketides, aspergiolides C (3) and D (4). Their constitutions were elucidated by a combination of spectroscopic methods and isotope‐labeling experiments. Aspergiolides C (3) and D (4) occur as racemic mixtures, the resolution of which was succeeded by HPLC on a chiral phase. The absolute configurations of their enantiomers were assigned online, from the peaks in the chromatogram, by a combination of HPLC‐CD and quantum chemical CD calculations. Both compounds were found to inhibit the kinase activities of the receptor tyrosine kinases (RTKs) c‐Met, Ron, and c‐Src with low‐micromolar IC50s. The enantiomers of 3were resolved by HPLC on a chiral phase. Both enantiomers showed a comparable inhibition of the HGF‐induced autophosphorylation of c‐Met and of subsequent cell migration.

Tubulin-binding agents have received considerable interest as potential anti-cancer drugs. These compounds interfere with tubulin dynamics and microtubule organization and thereby induce cell growth arrest at G2/M phase, and eventually lead to apoptotic cell death. Herein, we report that sulfated oligosaccharide JG3 was effective at inhibiting viability of cancer cells, and suppressing tumor growth in vivo. Our studies showed that JG3 significantly arrested cell cycle at G2/M phase and led cancer cells to apoptotic death. Consistent with this, tubulin was identified as a binding protein of JG3 using affinity chromatography and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The interaction between JG3 and tubulin was characterized by surface plasmon resonance (SPR) analysis. Furthermore, it was demonstrated both at cellular level and in cell free system that JG3 potently prevented tubulin polymerization, thereby demolished microtubule organization in cancer cells. The underlying mechanism lies in its binding to tubulin on a unique site distinct from other conventional binding sites. All these suggest that JG3 is a novel antimitotic reagent, and this might shed new light on the understanding of anti-cancer activities and mechanisms of novel antimitotic reagents, and help develop new antimitotic agents in cancer therapy.

Overexpression, point mutations, or translocations of protein lysine methyltransferase NSD2 occur in many types of cancer cells. Therefore, it was recognized as onco-protein and considered as a promising anticancer drug target. NSD2 consists of multiple domains including a SET catalytic domain and two PWWP domains binding to methylated histone proteins. Here, we reported our efforts to develop a series of NSD2-PWWP1 inhibitors, and further structure-based optimization resulted in a potent inhibitor 38, which has high selectivity toward the NSD2-PWWP1 domain. The detailed biological evaluation revealed that compound 38can bind to NSD2-PWWP1 and then affect the expression of genes regulated by NSD2. The current discovery will provide a useful chemical probe to the future research in understanding the specific regulation mode of NSD2 by PWWP1 recognition and pave the way to develop potential drugs targeting NSD2 protein.

As a complex pathogenesis driven by immune inflammatory factors and intestinal microbiota, the treatment of inflammatory bowel disease (IBD) may rely on the comprehensive regulation of these important pathogenic factors to reach a favorable therapeutic effect. In the current study, we discovered a series of imidazo[4,5-c]quinoline derivatives that potently and simultaneously inhibited two primary proinflammatory signaling pathways JAK/STAT and NF-κB. Especially, lead compound 8lshowed potent inhibitory activities against interferon-stimulated genes (IC50: 3.3 nM) and NF-κB pathways (IC50: 150.7 nM) and decreased the release of various proinflammatory factors at the nanomolar level, including IL-6, IL-8, IL-1β, TNF-α, IL-12, and IFN-γ. In vivo, 8lproduced a strong anti-inflammatory activity in both dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced acute enteritis models and restored the structural composition of gut microbiota. Collectively, this study provided valuable lead compounds for the treatment of IBD and revealed the great anti-inflammatory potential of the simultaneous suppression of JAK/STAT and NF-κB signals.

Abstract: Acidic oligosaccharide sugar chain (AOSC), a D-mannuronic acid oligosaccharide, derived from brown algae polysaccharide, has been completed Phase I clinical trial in China as an anti-Alzheimer’s Disease (AD) drug candidate. The identification of AOSC-binding protein(s) in neurons is very important for understanding its action mechanism. To determine the binding protein(s) of AOSC in neurons mediating its anti-AD activities, confocal microscopy, affinity chromatography, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis were used. Confocal microscopy analysis shows that AOSC binds to SH-SY5Y cells in concentration-, time-, and temperature-dependent fashions. The AOSC binding proteins were purified by affinity chromatography and identified by LC-MS/MS analysis. The results showed that there are 349 proteins binding AOSC, including clathrin, adaptor protein-2 (AP-2) and amyloid precursor protein (APP). These results suggest that the binding/entrance of AOSC to neurons is probably responsible for anti-AD activities.

Herein, we report that marine-derived sulfated polysaccharide (MSP), a new kind of polysaccharide extracted from brown alga, exhibits the anti-migration effect in vitro and potently suppress metastasis of Lewis lung carcinoma in vivo. Adhesion assays demonstrated that MSP inhibits the heterogenous adhesion on fibronectin. Further studies revealed that MSP decreased FN-induced MDA-MB-435 migration, accompanied by its potent regulatory effect on actin filament reassembling. In addition, MSP significantly inactivated the phosphorylation of FAK and subsequent ERK1/2 in MDA-MB-435 cells. All these actions may be the results of MSP binding to FN, promising the therapeutic potential of MSP in tumor metastasis.

Sulfated polymannuroguluronate (SPMG) has entered the phase II clinical trial as the first anti-AIDS drug candidate in China. Herein, we report that SPMG was effective at protecting T lymphocytes against apoptosis. Further studies indicated that SPMG significantly elevated mitochondrial membrane potential (MMP) of T cells; inhibited mitochondrial release of cytochrome c (cyto c) in T cells; enhanced the activities of mitochondrial enzyme complex I, III, and V; and subsequently increased ATP level and ATP/ADP ratio. In addition, SPMG potently suppressed reactive oxygen species (ROS) generation in mitochondria at cellular level and scavenged free radicals in cell-free system. The molecular mechanism underlying the ATP-involved and ROS-dependent antiapoptosis of SPMG is characterized as having been caused by its engagement with mitochondrial import receptor and ADP/ATP carrier in T-cell outer and inner mitochondrial membrane, respectively. All these might shed new light on the understanding of anti-AIDS functions of SPMG by protecting T cells of persons infected with human immunodeficiency virus.

In this paper, we investigated interactions of the acidic oligosaccharide sugar chain (AOSC), derived from brown algae Echlonia kuromeOKAM, with amyloid beta protein (Aβ). We observed that AOSC inhibited the toxicity induced by Aβin both primarily cortical cells and the SH-SY5Y cell line. We also observed that AOSC inhibited the apoptosis induced by Aβin SH-SY5Y by reducing the elevated level of intracellular calcium concentration ([Ca2+]i) and suppressing the generation of reactive oxygen species. Surface plasmon resonance analysis demonstrated that AOSC had affinity for both freshly-dissolved Aβand 48-h incubated Aβ. Furthermore, AOSC blocked the fibril formation of Aβ, which may be responsible for its anti-cytotoxic effects. Thus, our results indicate that AOSC might be a potentially therapeutic compound for Alzheimer’s disease.

Anti-proliferation action and enhancement of endothelial cell immunity and related mechanisms by marine sulfated polymannuroguluronate (SPMG) were investigated in the present studies. Endothelial cell proliferation was evaluated by MTT assay. Intercellular adhesion molecule-1 (ICAM-1) expression was analyzed by flow cytometry. The interaction of SPMG with basic fibroblast growth factor (bFGF) was evaluated by surface plasmon resonance. Results showed that SPMG exhibited a significant inhibitory effect against proliferation in both normal human umbilical vein endothelial cells (HUVEC) and bFGF-treated HUVEC, the action of which was completely abrogated by bFGF antibody. SPMG exerted high affinity to bFGF in a multivalent pattern, characterized by one molecule SPMG binding to 3 – 4 molecules of bFGF. Moreover, SPMG enhanced ICAM-1 expression in HUVEC and prevented and restored bFGF-treated downregulation of ICAM-1 expression in HUVEC, the expression of which was not counteracted by bFGF antibody. In conclusion, this is the first report demonstrating that SPMG exerted an anti-proliferation effect dependent on the bFGF-regulated pathway and afforded upregulatory activity on ICAM-1 expression regardless of the involvement of bFGF.

Blockade of immune checkpoint PD-1/PD-L1 has been a promising anticancer strategy; however, clinically available PD-1/PD-L1 small-molecule inhibitors are lacking. In view of the high potency of compound 2(BMS-1002), structural fine tuning of the methoxy linkage together with diverse modification in the solvent interaction region was conducted. A series of novel derivatives featuring a difluoromethyleneoxy linkage were designed. Compound 43was identified as the most promising PD-1/PD-L1 inhibitor with an IC50value of 10.2 nM in the HTRF assay. This compound is capable of promoting CD8+T cell activation through inhibiting PD-1/PD-L1 cellular signaling. Moreover, in the Hepa1-6 syngeneic mouse model, administration of compound 43at 1 mg/kg dosage promoted CD8+T cell activation and delayed the tumor growth with good tolerance. Notably, the tumor in one mouse of the compound 43-treated group was completely regressed. These results indicate that compound 43is a promising candidate worthy of further investigation.

Sulfated polymannuronate (SPMG), a novel anti-AIDS drug candidate, combats HIV-1 infection mainly by binding to gp120 protein with high affinity. To explore the structural basis of this anti-HIV-1 action, size-defined oligosaccharides were prepared by semi-synthesis or separated from native SPMG. In this study, a series of homogeneously sized SPMG fragments are evaluated for their capacity to bind rgp120 using surface plasmon resonance (SPR) analysis. The minimum SPMG fragment size that interacts with rgp120 is a hexasaccharide. Additionally, binding capacity increases with the molecular size of oligosaccharides, with the affinity of large fragments (≥ 15–16 saccharides) approaching that of full-sized SPMG. Competitive inhibition and stoichiometric analyses disclose that SPMG oligos bind to multiple binding sites on gp120. Sugar chains longer than 15–16 saccharide residues (SPMG) display multivalent interactions, with one sugar chain binding to two or three gp120 molecules. Consistent with binding data, a positive correlation exists between the size of SPMG oligosaccharides and their anti-HIV activity. The octasaccharide is established to be the minimal active fragment inhibiting syncytium formation and lowering the P24 core antigen level in HIV-IIIB-infected CEM cells. Alternatively, about 50% anti-HIV activity was observed for 15–16 saccharides, whereas a 19–20-saccharide fragment displayed anti-HIV activity equivalent to native SPMG. The structures of the unique minimum hexasaccharide specifically recognized by gp120 and the minimum octasaccharide combating HIV-IIIB infection were representatively structured as [ManA (2s)β1-4 ManA(2s/3s)]n.