1  INTRODUCTION
Coronaviruses (CoVs) infect humans and animals. In humans, CoVs cause primarily multiple respiratory and intestinal infections that can range from mild to lethal. 1 ,  2 ,  3  According to the International Committee on Taxonomy of Viruses (ICTV), CoVs constitute the family Coronaviridae under the order Nidovirales. Coronaviridae comprise two subfamilies, Torovirinae and Coronavirinae, the latter being further divided into four main genera: α‐, β‐, γ‐, and δ‐coronaviruses (Figure 1). 4  The history of human CoVs began in the 1930s, but only in the 1960s, the first human CoVs were identified in patients with mild respiratory infections, which were later named HCoV‐229E and HCoV‐OC43, belonging to α‐coronaviruses. 5 ,  6 ,  7  Since then, virologists have discovered new viruses, studying their infection mechanisms, as well as their replication, and pathogenesis. This led to the identification of five novel CoVs belonging to β‐coronaviruses that have crossed the species barrier to infect humans: HCoV‐Hong Kong University 1 (HKU1), HCoV‐NL63, severe‐acute respiratory syndrome (SARS)‐CoV‐1, Middle East respiratory syndrome (MERS)‐CoV, and SARS‐CoV‐2 (COVID‐19).
Figure 1  Schematic representation of the taxonomy of Coronaviridae (according to the International Committee on Taxonomy of Viruses). The seven human‐infecting coronaviruses belong to the α‐ or β‐coronavirus genus (highly infectious pathogens are highlighted red) [Color figure can be viewed at wileyonlinelibrary.com] The three last‐mentioned viruses are extremely dangerous because of their rapid transmission between humans. SARS‐CoV‐1, which emerged in 2002, affected 8096 in 32 countries, 774 of whom died (fatality rate 10%–15%). 8  MERS‐CoV, which appeared in 2012, affected a total of 1841 individuals, 652 of whom died with the mortality rate of ~35% worldwide. 9
The new coronavirus, known as SARS‐CoV‐2 or 2019‐nCoV has been identified as an etiological agent for the current epidemic with a contagious pneumonia‐like illness, spreading incredibly rapidly. As of July 15, 2020, the outbreak of SARS‐CoV‐2 has claimed more than 573 752 lives and infected more than 13 119 239 people around the planet. 10  Public life has come to a halt, as many governments impose social distancing strategies and lockdown to prevent further spread of the virus. To date, no targeted therapeutics or vaccines are approved, and effective treatment options against any human‐infecting CoVs remain very limited.

1.1  Infection cycle of human CoVs and their druggable targets
Human‐infecting CoVs belonging to the α‐ and β‐CoV genera infect only mammals. According to the sequence database, all human CoVs have animal origins; HCoV‐NL63, HCoV‐229E, SARS‐CoV‐1, SARS‐CoV‐2, and MERS‐CoV are suggested to have originated from bats; HCoV‐OC43 and HKU1‐CoV likely originated from rodents. 11 ,  12
CoVs are enveloped, single‐stranded, positive‐sense RNA viruses featuring the largest viral RNA genomes known to date, ranging roughly from 26 to 32 kilobases. The SARS‐CoV‐2 genome comprises ~30 000 nucleotides. 13  For the virus to spread, the information of its structural and functional proteins must be replicated and packed into new virus particles. Since the virus lacks the necessary infrastructure for this process, it is entirely dependent on its host organism to translate its RNA into proteins and make more RNA copies.
To infect its desired host cell, the virus uses its many spike (S) glycoproteins protruding from its membrane. 13  In general, the life cycle of CoVs can be classified into four main steps, including entry, replication, assembly, and release.
The infection cycle of a CoV (Figure 2) begins with its entry. Using the S glycoprotein, it attaches itself to a surface receptor of the host cell. The host cell receptor and its distribution determine which tissues get infected. The specificity of the S protein to a particular receptor influences viral tropism. CoVs use different human receptors as points of entry: SARS‐CoV‐1, SARS‐CoV‐2, and HCoV‐NL63 use angiotensin‐converting enzyme 2 (ACE2); 14 ,  15 ,  16  MERS‐CoV uses dipeptidyl peptidase‐4 (DPP4); 17  CoV‐22E uses aminopeptidase N; 18  and HCoV‐OC43 as well as HCoV‐HKUI use O‐acetylated sialic acid (see Table 1). 19 ,  20
Figure 2  Infection cycle of coronaviruses, for example, SARS‐CoV‐2. The figure was adapted with permission from Invivogen (https://www.invivogen.com/spotlight-covid-19-infection). SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2 [Color figure can be viewed at wileyonlinelibrary.com]
Table 1  Classification, discovery, cellular receptor, and natural intermediate host of the coronaviruses
HCoV genera  Coronaviruses  Discovery  Cellular receptor  Natural host(s)
α‐Coronaviruses  HCoV‐229E  1966  Human aminopeptidase N (CD13)  Bats
HCoV‐NL63  2004  ACE2  Palm civets, bats
β‐Coronaviruses  HCoV‐OC43  1967  9‐O‐Acetylated sialic acid  Cattle
HCoV‐HKU1  2005  9‐O‐Acetylated sialic acid  Mice
SARS‐CoV‐1  2003  ACE2  Palm civets
MERS‐CoV  2012  DPP4  Bats, camels
SARS‐CoV‐2  2019  ACE2  Bats, (?)
Note: ? indicate other possible hosts of SARS‐CoV‐2, besides bats ‐ if they exist ‐ have not been conclusively identified yet.
John Wiley & Sons, Ltd. This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency. When the spike protein attaches to its host cellular receptor, it is cleaved into two parts (S1 and S2) by extracellular proteases. While S1 remains attached to its target, S2 is further cleaved by the host cell's own transmembrane serine protease 2 (TMPRSS2). This process induces the fusion of the viral membrane with the host cell's membrane. 15
Upon fusion, the contents of the virus particle are released into the host cell's cytoplasm. The virus's genomic positive‐sense RNA, which comprises two overlapping open reading frames (ORFs), ORF1a and ORF1b, is quickly translated into two polyproteins, pp1a and pp1ab. These proteins are the so‐called replicase‐transcriptase‐complex, because of their role in replication and further transcription. The newly formed polyproteins are immediately autocatalytically proteolyzed into smaller proteins by two viral proteases, 3C‐like protease (3CLpro), otherwise known as main protease (Mpro), and papain‐like protease (PLpro). 21 ,  22
The cleavage products include 16 nonstructural proteins (nsp) like the RNA‐dependent RNA polymerase (RdRP) that facilitates the production of antisense RNA, as well as 4 structural proteins like the S glycoprotein, envelope (E) proteins, membrane proteins (M), and nucleocapsid (N) proteins. 21 ,  22 ,  23  Newly generated antisense RNA is used as a template for new copies of viral positive‐sense RNA as well as for the production of differently sized subgenomic mRNAs, which can be translated into new viral proteins at the endoplasmic reticulum. Finally, proteins and genomic RNA are assembled, packed into vesicles in the Golgi apparatus and exocytosed to the outside to repeat the process in surrounding cells. 23
This process does not pass unnoticed by the host organism, as infected cells present viral structures on their surface. As a response, many defensive pathways are initiated, such as the production of different cytokines and chemokines like interleukin 1 (IL‐1), IL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1. The release of these mediators and their effector cells activate inflammatory mechanisms to destroy the intruder. 24
The interruption of any stage of the viral life cycle can become an important therapeutic approach for treating CoV‐related diseases. A recent SARS‐CoV‐2‐human protein‐protein interaction analysis showed that SARS‐CoV‐2 contains approximately 66 druggable proteins, each of which has several ligand binding sites. 25  The most interesting coronavirus proteins are the S glycoprotein, proteases Mpro and PLpro, RdRP, and helicase. In this review, we highlight these targets with potential therapeutic development against the highly dangerous pathogens SARS‐CoV‐1 and 2, and MERS‐CoV. Medicinal chemistry efforts toward the evolution of molecules with drug‐like properties is additionally discussed. In addition, broad‐spectrum antivirals targeting the major viruses are reviewed in detail, since they represent a highly promising strategy for treating these often fatal respiratory illnesses.