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  • 1.
    Araújo, Ana Catarina
    et al.
    Univ Lisbon, Lisbon, Portugal .
    Rauter, Amelia P.
    Nicotra, Francesco
    Airoldi, Cristina
    Costa, Barbara
    Cipolla, Laura
    Sugar-Based Enantiomeric and Conformationally Constrained Pyrrolo[2,1-c][1,4]-Benzodiazepines as Potential GABA(A) Ligands2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 5, p. 1266-1275Article in journal (Refereed)
    Abstract [en]

    Synthesis of a library of pyrrolo[2,1-c][1,4]-benzodiazepines derived from spiro bicyclic D- or L-proline analogues containing a D- or L-fructose moiety was developed. The L-fructose moiety was obtained by using a new synthetic pathway starting from L-arabinose through a six steps synthesis in 18% overall yield. Molecular modeling calculations and DNMR studies showed that D- and L.-fructose-based pyrrolobenzodiazepines exhibit a rigid (P)- and (M)-helical conformation, respectively, in which the C-11a substituent was always pseudoequatorial. Additionally, pyrrolobenzodiazepines functionalized with a chloride, bromide, nitro, or amino group in the benzene ring, with or without N-methylation and with or without protection of sugar alcohol groups, allowed a relationship between the molecular structure and biological activity to be established. The conformation of the diazepam ring was not the sole key player influencing binding affinities, and the sugar moiety can in some cases increase the binding activity, possibly by compounds have increased the understanding of the differential recognition receptor. participating in the binding event. Finally, these of (M)-/(P)-helical benzodiazepines on GABA(A) receptor.

  • 2. Bunyapaiboonsri, T.
    et al.
    Ramstrom, H.
    Ramström, Olof
    KTH, Superseded Departments, Chemistry.
    Haiech, J.
    Lehn, J. M.
    Generation of Bis-cationic heterocyclic inhibitors of Bacillus subtilis HPr kinase/phosphatase from a ditopic dynamic combinatorial library2003In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 46, no 26, p. 5803-5811Article in journal (Refereed)
    Abstract [en]

    Ditopic dynamic combinatorial. libraries were generated and screened toward inhibition of the bifunctional enzyme HPr kinase/phosphatase from Bacillus subtilis. The libraries were composed of all possible combinations resulting from the dynamic interconversion of 16 hydrazides and five monoaldehyde or dialdehyde building blocks, resulting in libraries containing up to 440 different constituents. Of all possible acyl hydrazones formed, active compounds containing two terminal cationic heterocyclic recognition groups separated by a spacer of appropriate structure could be rapidly identified using a dynamic deconvolution procedure. Thus, parallel testing of sublibraries where one specific component was excluded basically revealed all the essential components. A potent ditopic inhibitor, based on 2-amino-benzimidazole, was identified from the process.

  • 3.
    Dinér, Peter
    et al.
    University of Gothenburg.
    Alao, John Patrick
    Söderlund, Johan
    Sunnerhagen, Per
    Grøtli, Morten
    Preparation of 3-Substituted-1-Isopropyl-1H-pyrazolo 3,4-d pyrimidin-4-amines as RET Kinase Inhibitors2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55 4872-4876, no 10, p. 4872-4876Article in journal (Refereed)
  • 4. Dyrager, Christine
    et al.
    Nilsson Möllers, Linda
    Kjäll, Linda Karlsson
    Alao, John Patrick
    Dinér, Peter
    University of Gothenburg.
    Wallner, Fredrik
    Sunnerhagen, Per
    Grøtli, Morten
    Möllers, Linda N
    Design, synthesis, and biological evaluation of chromone-based p38 MAP kinase inhibitors2011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54Article in journal (Refereed)
  • 5.
    Hofström, Camilla
    et al.
    KTH, School of Biotechnology (BIO), Protein Technology.
    Altai, Mohamed
    Honarvar, Hadis
    Strand, Joanna
    Malmberg, Jennie
    Hosseinimehr, Seyed Jalal
    Orlova, Anna
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Protein Technology.
    Tolmachev, Vladimir
    HAHAHA, HEHEHE, HIHIHI, or HKHKHK: Influence of Position and Composition of Histidine Containing Tags on Biodistribution of [Tc-99m(CO)(3)](+)-Labeled Affibody Molecules2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 12, p. 4966-4974Article in journal (Refereed)
    Abstract [en]

    Engineered affibody molecules can be used for high contrast in vivo molecular imaging. Extending a recombinantly produced HER2 binding affibody molecule with a hexa-histidine tag allows for convenient purification by immobilized metal-ion affinity chromatography and labeling with [Tc-99m(CO)(3)](+) but increases radioactivity uptake in the liver. To investigate the impact of charge, lipophilicity, and position on biodistribution, 10 variants of a histidine-based tag was attached to a HER2 binding affibody molecule. The biochemical properties and the HER2 binding affinity appeared to be similar for all variants. In vivo, positive charge promoted liver uptake. For N-terminally placed tags, promoted liver uptake and decreased kidney uptake. Kidney uptake was higher for C-terminally placed tags compared to their N-terminal counterparts. The variant with the amino acid composition HEHEHE placed in the N-terminus gave the lowest nonspecific uptake.

  • 6.
    Hofström, Camilla
    et al.
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Orlova, Anna
    Altai, Mohamed
    Wångsell, Fredrik
    Gräslund, Torbjörn
    KTH, School of Biotechnology (BIO), Molecular Biotechnology.
    Tolmachev, Vladimir
    Use of a HEHEHE Purification Tag Instead of a Hexahistidine Tag Improves Biodistribution of Affibody Molecules Site-Specifically Labeled with Tc-99m, In-111 and I-1252011In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 54, no 11, p. 3817-3826Article in journal (Refereed)
    Abstract [en]

    Affibody molecules are a class of small (similar to 7 kDa) robust scaffold proteins suitable for radionuclide molecular imaging in vivo. The attachment of a hexahistidine (His(6))-tag to the Affibody molecule allows facile purification by immobilized metal ion affinity chromatography (IMAC) but leads to high accumulation of radioactivity in the liver. Earlier, we have demonstrated that replacement of the His(6)- tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine-glutamate (HEHEHE)-tag permits purification of Affibody molecules by IMAC, enables labeling with [Tc-99m(CO)(3)](+), and provides low hepatic accumulation of radioactivity. In this study, we compared the biodistribution of cysteine-containing Affibody molecules site-specifically labeled with In-111, Tc-99m, and I-125 at the C-terminus, having a His(6)-tag at the N- or C-terminus or a HEHEHE-tag at the N-terminus. We show that the use of a HEHEHE-tag provides appreciable reduction of hepatic radioactivity, especially for radiometal labels. We hope that this information can also be useful for development of other scaffold protein-based imaging agents.

  • 7.
    Jacobsson, Micael
    et al.
    Uppsala universitet, Avdelningen för organisk farmaceutisk kemi.
    Lidén, Per
    Stjernschantz, Eva
    Boström, Henrik
    Stockholm University, Sweden.
    Norinder, Ulf
    Improving structure-based virtual screening by multivariate analysis of scoring data2003In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 46, no 26, p. 5781-5789Article in journal (Refereed)
    Abstract [en]

    hree different multivariate statistical methods, PLS discriminant analysis, rule-based methods, and Bayesian classification, have been applied to multidimensional scoring data from four different target proteins: estrogen receptor alpha (ERalpha), matrix metalloprotease 3 (MMP3), factor Xa (fXa), and acetylcholine esterase (AChE). The purpose was to build classifiers able to discriminate between active and inactive compounds, given a structure-based virtual screen. Seven different scoring functions were used to generate the scoring matrices. The classifiers were compared to classical consensus scoring and single scoring functions. The classifiers show a superior performance, with rule-based methods being most effective. The precision of correctly predicting an active compound is about 90% for three of the targets and about 25% for acetylcholine esterase. On the basis of these results, a new two-stage approach is suggested for structure-based virtual screening where limited activity information is available.

  • 8.
    Kang, Dongwei
    et al.
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Zhang, Heng
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Wang, Zhao
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Zhao, Tong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ginex, Tiziana
    Univ Barcelona, Inst Biomed IBUB, Fac Pharm, Dept Nutr Food Sci & Gastron, Campus Torribera, Santa Coloma De Gramenet 08921, Spain.;Univ Barcelona, Inst Theoret & Computat Chem IQTCUB, Campus Torribera, Santa Coloma De Gramenet 08921, Spain..
    Luque, Francisco Javier
    Univ Barcelona, Inst Biomed IBUB, Fac Pharm, Dept Nutr Food Sci & Gastron, Campus Torribera, Santa Coloma De Gramenet 08921, Spain.;Univ Barcelona, Inst Theoret & Computat Chem IQTCUB, Campus Torribera, Santa Coloma De Gramenet 08921, Spain..
    Yang, Yang
    Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA..
    Wu, Gaochan
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Feng, Da
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Wei, Fenju
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Zhang, Jian
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    De Clercq, Erik
    Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, Herestr 49 Postbus 1043 09-A097, B-3000 Leuven, Belgium..
    Pannecouque, Christophe
    Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, Herestr 49 Postbus 1043 09-A097, B-3000 Leuven, Belgium..
    Chen, Chin Ho
    Duke Univ, Med Ctr, Surg Oncol Res Facil, Box 2926, Durham, NC 27710 USA..
    Lee, Kuo-Hsiung
    Univ N Carolina, Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA.;China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung 40402, Taiwan..
    Murugan, N. Arul
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Steitz, Thomas A.
    Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA..
    Zhan, Peng
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Liu, Xinyong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Identification of Dihydrofuro[3,4-d]pyrimidine Derivatives as Novel HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors with Promising Antiviral Activities and Desirable Physicochemical Properties2019In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 3, p. 1484-1501Article in journal (Refereed)
    Abstract [en]

    To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and "tolerant region II" of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4-d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC50 = 0.9-8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance. [GRAPHICS]

  • 9.
    Ti, Huihui
    et al.
    Guangzhou Med Univ, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Sch Pharmaceut Sci, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China..
    Zhou, Yang
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology. Guangzhou Med Univ, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Sch Pharmaceut Sci, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China.
    Liang, Xue
    Guangzhou Med Univ, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Sch Pharmaceut Sci, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China..
    Li, Runfeng
    Guangzhou Med Univ, State Key Lab Resp Dis, Natl Clin Res Ctr Resp Dis, Guangzhou Inst Resp Hlth,Affiliated Hosp 1, Guangzhou 510120, Guangdong, Peoples R China..
    Ding, Ke
    Jinan Univ, Int Cooperat Lab Tradit Chinese Med Modernizat &, Chinese Minist Educ MOE, Sch Pharm,Guangzhou City Key Lab Precis Chem Drug, Guangzhou 510632, Guangdong, Peoples R China.;Guangzhou Med Univ, State Key Lab Resp Dis, Natl Clin Res Ctr Resp Dis, Guangzhou Inst Resp Hlth,Affiliated Hosp 1, Guangzhou 510120, Guangdong, Peoples R China..
    Zhao, Xin
    Guangzhou Med Univ, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Sch Pharmaceut Sci, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China.;Chinese Univ Hong Kong, Sch Life Sci, Shatin, Hong Kong 999077, Peoples R China..
    Targeted Treatments for Chronic Obstructive Pulmonary Disease (COPD) Using Low-Molecular-Weight Drugs (LMWDs)2019In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, no 13, p. 5944-5978Article in journal (Refereed)
    Abstract [en]

    Chronic obstructive pulmonary disease (COPD) is a very common and frequently fatal airway disease. Current therapies for COPD depend mainly on long-acting bronchodilators, which cannot target the pathogenic mechanisms of chronic inflammation in COPD. New pharmaceutical therapies for the inflammatory processes of COPD are urgently needed. Several anti-inflammatory targets have been identified based on increased understanding of the pathogenesis of COPD, which raises new hopes for targeted treatment of this fatal respiratory disease. In this review, we discuss the recent advances in bioactive low-molecular-weight drugs (LMWDs) for the treatment of COPD and, in addition to the first-line drug bronchodilators, focus particularly on low-molecular-weight anti-inflammatory agents, including modulators of inflammatory mediators, inflammasome inhibitors, protease inhibitors, antioxidants, PDE4 inhibitors, kinase inhibitors, and other agents. We also provide new insights into targeted COPD treatments using LMWDs, particularly small-molecule agents.

  • 10. Zhang, J.
    et al.
    Natarajan Arul, Murugan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Tian, Y.
    Bertagnin, C.
    Fang, Z.
    Kang, D.
    Kong, X.
    Jia, H.
    Sun, Z.
    Jia, R.
    Gao, P.
    Poongavanam, V.
    Loregian, A.
    Xu, W.
    Ma, X.
    Ding, X.
    Huang, B.
    Zhan, P.
    Liu, X.
    Structure-Based Optimization of N-Substituted Oseltamivir Derivatives as Potent Anti-Influenza A Virus Agents with Significantly Improved Potency against Oseltamivir-Resistant N1-H274Y Variant2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 22, p. 9976-9999Article in journal (Refereed)
    Abstract [en]

    Due to the emergence of highly pathogenic and oseltamivir-resistant influenza viruses, there is an urgent need to develop new anti-influenza agents. Herein, five subseries of oseltamivir derivatives were designed and synthesized to improve their activity toward drug-resistant viral strains by further exploiting the 150-cavity in the neuraminidases (NAs). The bioassay results showed that compound 21h exhibited antiviral activities similar to or better than those of oseltamivir carboxylate (OSC) against H5N1, H5N2, H5N6, and H5N8. Besides, 21h was 5- to 86-fold more potent than OSC toward N1, N8, and N1-H274Y mutant NAs in the inhibitory assays. Computational studies provided a plausible rationale for the high potency of 21h against group-1 and N1-H274Y NAs. In addition, 21h demonstrated acceptable oral bioavailability, low acute toxicity, potent antiviral activity in vivo, and high metabolic stability. Overall, the above excellent profiles make 21h a promising drug candidate for the treatment of influenza virus infection.

  • 11.
    Zhang, Jian
    et al.
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Poongavanam, Vasanthanathan
    Univ Southern Denmark, Dept Phys Chem & Pharm, DK-5230 Odense M, Denmark.;Uppsala Univ, Dept Chem BMC, Box 576, SE-75123 Uppsala, Sweden..
    Kang, Dongwei
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Bertagnin, Chiara
    Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy..
    Lu, Huamei
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Kong, Xiujie
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ju, Han
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Lu, Xueyi
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Gao, Ping
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Tian, Ye
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Jia, Haiyong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Desta, Samuel
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ding, Xiao
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Sun, Lin
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Fang, Zengjun
    Shandong Univ, Hosp 2, 247 Beiyuan Ave, Jinan 250033, Shandong, Peoples R China..
    Huang, Boshi
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Liang, Xuewu
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Jia, Ruifang
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Ma, Xiuli
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Xu, Wenfang
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Natarajan Arul, Murugan
    KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
    Loregian, Arianna
    Univ Padua, Dept Mol Med, Via Gabelli 63, I-35121 Padua, Italy..
    Huang, Bing
    Shandong Acad Agr Sci, Inst Poultry Sci, 1 Jiaoxiao Rd, Jinan 250023, Shandong, Peoples R China..
    Zhan, Peng
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Liu, Xinyong
    Shandong Univ, Sch Pharmaceut Sci, Minist Educ, Dept Med Chem,Key Lab Chem Biol, 44 West Culture Rd, Jinan 250012, Shandong, Peoples R China..
    Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and-2 Influenza A Neuraminidases, Including a Drug-Resistant Variant2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 14, p. 6379-6397Article in journal (Refereed)
    Abstract [en]

    On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

  • 12.
    Zhao, Xin
    et al.
    Guangzhou Med Univ, Sch Pharmaceut Sci, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China.;Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Guangdong, Peoples R China.;Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA..
    Li, Runfeng
    Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China..
    Zhou, Yang
    AlbaNova Univ Ctr, Royal Inst Technol KTH, Sch Biotechnol, Div Theoret Chem & Biol, SE-10044 Stockholm, Sweden..
    Xiao, Mengjie
    Guangzhou Med Univ, Sch Pharmaceut Sci, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China.;Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Guangdong, Peoples R China..
    Ma, Chunlong
    Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA.;Univ Arizona, BIO5 Inst, Tucson, AZ 85721 USA..
    Yang, Zhongjin
    Guangzhou Med Univ, Sch Pharmaceut Sci, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China..
    Zeng, Shaogao
    Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Guangdong, Peoples R China..
    Du, Qiuling
    Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China..
    Yang, Chunguang
    Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China..
    Jiang, Haiming
    Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China..
    Hu, Yanmei
    Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA.;Univ Arizona, BIO5 Inst, Tucson, AZ 85721 USA..
    Wang, Kefeng
    Guangzhou Med Univ, Sch Pharmaceut Sci, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China..
    Mok, Chris Ka Pun
    Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China.;Univ Hong Kong, HKU Li Ka Shing Fac Med, Sch Publ Hlth, HKU Pasteur Res Pole, 5 Sassoon Rd, Hong Kong, Peoples R China..
    Sun, Ping
    Guangzhou Med Univ, Sch Pharmaceut Sci, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China..
    Dong, Jianghong
    Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Guangdong, Peoples R China..
    Cui, Wei
    Wang, Jun
    Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA.;Univ Arizona, BIO5 Inst, Tucson, AZ 85721 USA..
    Tu, Yaoquan
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.
    Yang, Zifeng
    Guangzhou Med Univ, Guangzhou Inst Resp Hlth, Affiliated Hosp 1, Natl Clin Res Ctr Resp Dis,State Key Lab Resp Dis, Guangzhou 510120, Guangdong, Peoples R China..
    Hu, Wenhui
    Guangzhou Med Univ, Sch Pharmaceut Sci, Key Lab Mol Target & Clin Pharmacol, State Key Lab Resp Dis, Guangzhou 511436, Guangdong, Peoples R China.;Guangzhou Med Univ, Affiliated Hosp 5, Guangzhou 511436, Guangdong, Peoples R China.;Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510530, Guangdong, Peoples R China..
    Discovery of Highly Potent Pinanamine-Based Inhibitors against Amantadine- and Oseltamivir-Resistant Influenza A Viruses2018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 12, p. 5187-5198Article in journal (Refereed)
    Abstract [en]

    Influenza pandemic is a constant major threat to public health caused by influenza A viruses (IAVs). IAVs are subcategorized by the surface proteins hemagglutinin (HA) and neuraminidase (NA), in which they are both essential targets for drug discovery. While it is of great concern that NA inhibitor oseltamivir resistant strains are frequently identified from human or avian influenza virus, structural and functional characterization of influenza HA has raised hopes for new antiviral therapies. In this study, we explored a structure-activity relationship (SAR) of pinanamine-based antivirals and discovered a potent inhibitor M090 against amantadine-resistant viruses, including the 2009 H1N1 pandemic strains, and oseltamivir-resistant viruses. Mechanism of action studies, particularly hemolysis inhibition, indicated that M090 targets influenza HA and it occupied a highly conserved pocket of the HA(2) domain and inhibited virus-mediated membrane fusion by "locking" the bending state of HA(2) during the conformational rearrangement process. This work provides new binding sites within the HA protein and indicates that this pocket may be a promising target for broad-spectrum anti-influenza A drug design and development.

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