Current progress in antiviral strategies

Abstract

The prevalence of chronic viral infectious diseases, such as human immunodeficiency virus (HIV), hepatitis C virus (HCV), and influenza virus; the emergence and re-emergence of new viral infections, such as picornaviruses and coronaviruses; and, particularly, resistance to currently used antiviral drugs have led to increased demand for new antiviral strategies and reagents. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host factors. Virus-targeting antivirals can function directly or indirectly to inhibit the biological functions of viral proteins, mostly enzymatic activities, or to block viral replication machinery. Host-targeting antivirals target the host proteins that are involved in the viral life cycle, regulating the function of the immune system or other cellular processes in host cells. Here we review key targets and considerations for the development of both antiviral strategies.

Keywords: direct virus-targeting antiviral; host-targeting antiviral; indirect virus-targeting antiviral.

Figure 1

A schematic representation of the viral life cycle. The life cycle of a virus can be divided into six basic steps: 1. receptor or co-receptor binding; 2. fusion; 3. release of the viral genome; 4. translation of viral proteins; 5. genome multiplication; and 6. assembly, packaging, and release of the progeny virus. Because viral life cycles have extremely large discrepancies according to the type of virus, we refer the readers to find more detail in .

Figure 2

Mechanisms for antivirals targeting HIV-1 entry. (A) The crystal structure of HIV-1 gp120 with a complete V3 loop (PDB code: 2B4C[144]) is shown as a colored cartoon diagram covered by a transparent molecular surface. The gp120 molecule is colored in blue, and the CD4-binding site is highlighted in red. (B) The architecture of the HIV-1 Env (gp120–gp41) trimer presented as a cryo-EM map shown from a perspective parallel to the viral membrane . The relative positions of gp120 and gp41 are circled. (C) The crystal structure of the HIV-1 gp41 fusion core (PDB code: 1DLB). HR1 and HR2 are colored green and blue, respectively. The core formed by the three HR1 and two HR2 fragments is covered with a molecular surface, whereas the remaining HR2 fragment is shown as a cartoon diagram. The binding site for the HR2 region is highlighted in red. (B) Reproduced and modified, with permission, from . Abbreviations: HIV, human immunodeficiency virus; PDB, Protein Data Bank; cryo-EM, cryo-electron microscopy; HR, heptad repeat domain.

Figure 3

Pocket factor-binding site as a target for antivirals against picornaviral uncoating. The crystal structure of one structural unit, viral structural proteins 1 to 4 (VP1–4), of the enterovirus 71 (EV71) virus is shown as a cartoon diagram with VP1–4 depicted in blue, red, green, and yellow, respectively. The hydrophobic pocket (blue mesh) in VP1 EV71 is occupied by a natural lipid (magenta). The inset shows an enlarged structural comparison of the hydrophobic pockets of the mature virus (gray, with pocket factor shown in magenta) and empty particles (blue). Reproduced and modified, with permission, from .

Figure 4

The sites in HIV-1 integrase targeted by antivirals. The crystal structure of the two dimeric HIV-1 integrase core domains are shown as a cartoon diagram covered with a transparent molecular surface and colored as blue and green (PDB code: 3ZSQ). The binding sites for INSTIs and LEDGINs are colored gold and red, respectively. Abbreviations: HIV, human immunodeficiency virus; PDB, Protein Data Bank; INSTI, integrase strand transfer inhibitor; LEDGIN, lens epithelium-derived growth factor (LEDGF)/p75 binding site of integrase.

Figure 5

The sites in DENV MTase targeted by antivirals. The crystal structure of DENV MTase (PDB code: 3P8Z) is shown as a blue cartoon covered with transparent molecular surface. The SAM binding site, GTP binding site, and low-affinity site are highlighted in red, gold, and magenta, respectively. Abbreviations: DENV, dengue virus; PDB, Protein Data Bank; SAM, S-adenosyl methionine; MTase, methyltransferase.