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J Biomed Sci. 2019 Oct 23;26(1):84. doi: 10.1186/s12929-019-0567-0. [h=1]Development of effective anti-influenza drugs: congeners and conjugates - a review.[/h]
Shie JJ[SUP]1[/SUP], Fang JM[SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h] 1 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan. 2 Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan. jmfang@ntu.edu.tw. 3 The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan. jmfang@ntu.edu.tw.
[h=3]Abstract[/h] Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses, including the resistant strains. Relenza™ (zanamivir), Tamiflu™ (the phosphate salt of oseltamivir), Inavir™ (laninamivir octanoate) and Rapivab™ (peramivir) are four anti-influenza drugs targeting the viral neuraminidases (NAs). However, some problems of these drugs should be resolved, such as oral availability, drug resistance and the induced cytokine storm. Two possible strategies have been applied to tackle these problems by devising congeners and conjugates. In this review, congeners are the related compounds having comparable chemical structures and biological functions, whereas conjugate refers to a compound having two bioactive entities joined by a covalent bond. The rational design of NA inhibitors is based on the mechanism of the enzymatic hydrolysis of the sialic acid (Neu5Ac)-terminated glycoprotein. To improve binding affinity and lipophilicity of the existing NA inhibitors, several methods are utilized, including conversion of carboxylic acid to ester prodrug, conversion of guanidine to acylguanidine, substitution of carboxylic acid with bioisostere, and modification of glycerol side chain. Alternatively, conjugating NA inhibitors with other therapeutic entity provides a synergistic anti-influenza activity; for example, to kill the existing viruses and suppress the cytokines caused by cross-species infection.
[h=4]KEYWORDS:[/h] Congener; Conjugate; Drug; Influenza; Inhibitor; Neuraminidase
PMID: 31640786 DOI: 10.1186/s12929-019-0567-0
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Shie JJ[SUP]1[/SUP], Fang JM[SUP]2,[/SUP][SUP]3[/SUP].
[h=3]Author information[/h] 1 Institute of Chemistry, Academia Sinica, Taipei, 115, Taiwan. 2 Department of Chemistry, National Taiwan University, Taipei, 106, Taiwan. jmfang@ntu.edu.tw. 3 The Genomics Research Center, Academia Sinica, Taipei, 115, Taiwan. jmfang@ntu.edu.tw.
[h=3]Abstract[/h] Influenza is a long-standing health problem. For treatment of seasonal flu and possible pandemic infections, there is a need to develop new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses, including the resistant strains. Relenza™ (zanamivir), Tamiflu™ (the phosphate salt of oseltamivir), Inavir™ (laninamivir octanoate) and Rapivab™ (peramivir) are four anti-influenza drugs targeting the viral neuraminidases (NAs). However, some problems of these drugs should be resolved, such as oral availability, drug resistance and the induced cytokine storm. Two possible strategies have been applied to tackle these problems by devising congeners and conjugates. In this review, congeners are the related compounds having comparable chemical structures and biological functions, whereas conjugate refers to a compound having two bioactive entities joined by a covalent bond. The rational design of NA inhibitors is based on the mechanism of the enzymatic hydrolysis of the sialic acid (Neu5Ac)-terminated glycoprotein. To improve binding affinity and lipophilicity of the existing NA inhibitors, several methods are utilized, including conversion of carboxylic acid to ester prodrug, conversion of guanidine to acylguanidine, substitution of carboxylic acid with bioisostere, and modification of glycerol side chain. Alternatively, conjugating NA inhibitors with other therapeutic entity provides a synergistic anti-influenza activity; for example, to kill the existing viruses and suppress the cytokines caused by cross-species infection.
[h=4]KEYWORDS:[/h] Congener; Conjugate; Drug; Influenza; Inhibitor; Neuraminidase
PMID: 31640786 DOI: 10.1186/s12929-019-0567-0
Free full text