COVID-19 outbreak: history, mechanism, transmission, structural studies and therapeutics

Abstract

Purpose: The coronavirus outbreak emerged as a severe pandemic, claiming more than 0.8 million lives across the world and raised a major global health concern. We survey the history and mechanism of coronaviruses, and the structural characteristics of the spike protein and its key residues responsible for human transmissions.

Methods: We have carried out a systematic review to summarize the origin, transmission and etiology of COVID-19. The structural analysis of the spike protein and its disordered residues explains the mechanism of the viral transmission. A meta-data analysis of the therapeutic compounds targeting the SARS-CoV-2 is also included.

Results: Coronaviruses can cross the species barrier and infect humans with unexpected consequences for public health. The transmission rate of SARS-CoV-2 infection is higher compared to that of the closely related SARS-CoV infections. In SARS-CoV-2 infection, intrinsically disordered regions are observed at the interface of the spike protein and ACE2 receptor, providing a shape complementarity to the complex. The key residues of the spike protein have stronger binding affinity with ACE2. These can be probable reasons for the higher transmission rate of SARS-CoV-2. In addition, we have also discussed the therapeutic compounds and the vaccines to target SARS-CoV-2, which can help researchers to develop effective drugs/vaccines for COVID-19. The overall history and mechanism of entry of SARS-CoV-2 along with structural study of spike-ACE2 complex provide insights to understand disease pathogenesis and development of vaccines and drugs.

Keywords: COVID-19; Coronavirus; Epidemiology; Intrinsic disorder region; SARS-CoV; SARS-CoV-2 therapeutics; Spike protein.

Fig. 1

a Domain arrangement of SARS-CoV-2 spike protein. SS signal sequence, NTD N-terminal transactivation domain, RBD receptor binding domain, SD subdomain, FP fusion peptides, HR1 heptad repeat 1, HR2 heptad repeat 2, CD connector domain, S1/S2 and S2′ protease cleavage sites, TM transmembrane domain, CT cytoplasmic tail. b Host cell entry and replication of SARS-CoV-2. SARS-CoV-2 infection starts with the binding of spike protein with ACE2 receptor and the invasion process is triggered by host cell proteases (furin, trypsin, TMPRSS2 and cathepsin). SARS-CoV-2 releases RNA into the host cell, and the RNA is translated into viral replicase polyproteins pp1a and pp1ab, and subsequently cleaves into NSPs. The full-length negative strand RNA copies of the viral genome are produced by the enzyme replicase using the full-length positive-strand RNA genome as a template. During transcription, RNA polymerase produces a series of subgenomic mRNAs and translates into viral proteins [S (Spike), E (Envelope), N (Nucleocapsid), and M (Membrane)]. The viral proteins and the genome RNA are assembled into virions in Golgi and ER (endoplasmic reticulum), which are budding into ERGIC (ER–Golgi intermediate compartment) and released out of the cell via vesicles

Fig. 2

Inactive and active state conformations of spike protein with its receptor binding. a, b Represent the inactive state conformations in which S2 subunits (stem portion) are completely covered by the “down” position of CTD1s (head portion). It causes steric clashes and inhibits the binding between spike protein and ACE2. c Represents the active state conformation, in which one of the CTD1s is in open state (shown in red stars) and facilitates the binding between spike protein and ACE2. TM and CT stands for transmembrane domain and cytoplasmic tail, respectively

Fig. 3

Structure of the monomeric spike protein (green)—ACE2 receptor (blue) complex. The interface residues are shown in light golden. The disordered-to-ordered transition residues (Leu455 to Pro491 and Asn501 to Val503) have been marked in the figure