Development of effective anti-influenza drugs: congeners and conjugates - a review

Abstract

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.

Keywords: Congener; Conjugate; Drug; Influenza; Inhibitor; Neuraminidase.

Fig. 1

Timeline showing influenza pandemics caused by influenza A viruses

Fig. 2

Schematic representation of the life cycle of influenza virus

Fig. 3

Actions of hemagglutinin and neuraminidase. a Binding of HA to the surface Neu5Ac-linked glycoproteins on host cell. b NA catalyzes the hydrolytic reaction to cleave the terminal Neu5Ac residue from the sialo-receptor

Fig. 4

Chemical structures of currently available licensed anti-flu drugs. a M2 ion-channel inhibitors, b neuraminidase inhibitors, and c nucleoprotein inhibitor

Fig. 5

Substrates for assays of influenza NA inhibitors. a fluorescent substrate 2-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid (MUNANA), and b luminescent substrate NA-Star™

Fig. 6

Key interactions of NA inhibitors in the active site based on the crystal structures of the NA–inhibitor complexes. a NA–DANA complex; b NA–ZA complex

Fig. 7

Tackling the hydrophilic guanidinium group in zanamivir and guanidine-oseltamivir carboxylate. a Using 1-hydroxy-2-naphthoic acid to form ion-pair. b Forming acylguanidine as prodrug

Fig. 8

Influenza virus NA inhibitors based on bioisostere-substituted surrogates of sialic acid

Fig. 9

A practical synthesis of zanaphosphor. (a) Ac₂O, py, rt., 12 h; (b) 100 °C, 5 h, 50% yield for two steps; (c) TMSOTf, P(OEt)₂OTMS, 0 °C to rt., 24 h, 62% yield; (d) NBS, CH₂Cl₂, hv; (e) py, 50 °C, 1 h, 75% yield for two steps; (f) conc. H₂SO₄, Ac₂O, AcOH, rt., 48 h; 80% yield; (g) TMSN₃; (h) H₂, Lindlar cat.; (i) MeS-C(=NBoc)NHBoc, HgCl₂, Et₃N, CH₂Cl₂; (j) TMSBr, CH₂Cl₂; (k) MeONa, MeOH, 55% yield for 5 steps. Boc = tert-butoxycarbonyl, NBS = N-bromosuccinimide, py = pyridine, TMS = trimethylsilyl, TMSOTf = trimethylsilyl trifluoromethanesulfonate

Fig. 10

Strategies for synthesis of oseltamivir (OS, 5), tamiphosphor (TP, 22), tamiphosphor monoethyl ester (TP1Et, 23), guanidino tamiphosphor (TPG, 24) and guanidino tamiphosphor monoethyl ester (TPG1Et, 25)

Fig. 11

Synthesis of peraphosphor (PP, 33) and the monoethyl ester (PP1Et, 34) via a key step of [3 + 2] cycloaddition of 2-ethylbutanenitrile oxide with a cyclopentene dipolarophile

Fig. 12

Synthesis of oseltamivir boronates (36a/36b), trifluoroborates (37a/37b), sulfinates (39a/39b), sulfonates (40a/40b) and sulfones (42a/42b) from oseltamivir carboxylic acid (OC)

Fig. 13

Modification of zanamivir at the glycerol side chain. The C₇-OH group points away from the NA active site according to the crystallographic analysis of the ZA–NA complex [103]

Fig. 14

A strategy to kill influenza virus by ZA–porphyrin conjugate. ZA carries the conjugate 46 to viral surface through binding with neuraminidase, and porphyrin is light sensitized (λ_max = 420 nm) to generate singlet oxygen in close proximity, causing inactivation of influenza virus

Fig. 15

Enhanced anti-influenza activity of ZA−caffeate and PE−caffeate conjugates by synergistic inhibition of neuraminidase and suppression of the virus-induced cytokines