Highlights in antiviral drug research: antivirals at the horizon

Abstract

This review highlights ten "hot topics" in current antiviral research: (i) new nucleoside derivatives (i.e., PSI-352938) showing high potential as a direct antiviral against hepatitis C virus (HCV); (ii) cyclopropavir, which should be further pursued for treatment of human cytomegalovirus (HCMV) infections; (iii) North-methanocarbathymidine (N-MCT), with a N-locked conformation, showing promising activity against both α- and γ-herpesviruses; (iv) CMX001, an orally bioavailable prodrug of cidofovir with broad-spectrum activity against DNA viruses, including polyoma, adeno, herpes, and pox; (v) favipiravir, which is primarily pursued for the treatment of influenza virus infections, but also inhibits the replication of other RNA viruses, particularly (-)RNA viruses such as arena, bunya, and hanta; (vi) newly emerging antiarenaviral compounds which should be more effective (and less toxic) than the ubiquitously used ribavirin; (vii) antipicornavirus agents in clinical development (pleconaril, BTA-798, and V-073); (viii) natural products receiving increased attention as potential antiviral drugs; (ix) antivirals such as U0126 targeted at specific cellular kinase pathways [i.e., mitogen extracellular kinase (MEK)], showing activity against influenza and other viruses; and (x) two structurally unrelated compounds (i.e., LJ-001 and dUY11) with broad-spectrum activity against virtually all enveloped RNA and DNA viruses.

Keywords: CMX001; LJ-001; N-MCT; PSI-352938; U0126; antiarenaviral; antipicornaviral; cyclopropavir; dUY11; favipiravir; natural products.

Figure 1

Structures of nucleoside analogues and their prodrugs active against HCV NS5B polymerase.

Figure 2

Structures of cyclopropavir, valcyclopropavir, and the cyclic phosphonate of cyclopropavir.

Figure 3

Structures of carbocyclic thymidine, North‐methanocarbathymidine (N‐MCT), South‐methanocarbathymidine (S‐MCT), and D‐(+)‐iso‐methanocarbathymidine (D‐(+)‐iso‐MCT).

Figure 4

Structures of cidofovir (CDV) and HDP‐CDV (CMX001).

Figure 5

Structures of T‐705, T‐1105, and T‐1106, and of T‐705 metabolites.

Figure 6

Arenavirus inhibitors targeted at viral entry.

Figure 7

Structures of pleconaril, BTA‐798, and V‐073.

Figure 8

Structures of natural products.

Figure 9

Structures of MEK inhibitors U0126, PD 184352, PD 0325901, and PD 098059.

Figure 10

Structures of dUY11 and LJ‐001.