Emergence and Re-emergence of Human Coronaviruses: Spike Protein as the Potential Molecular Switch and Pharmaceutical Target
Authors: Ahmad Fahim , Kamal Mohammad A. , Tekwani Babu L. 
Published: January 2021

Background:
Recent emergence of COVID-19 caused by a new human coronavirus (CoV) strain
(SARS-CoV-2), which originated from China, poses the future emergence of additional CoVs. In most of the
cases of emergence of human CoVs, bats, palm civets, raccoon dogs and camels have been identified as the
sources of human infections and as reservoir hosts. A review of comparative genomic and phenotypic characteristics
of human CoV strains vis-à-vis their comparison with the corresponding animal isolates shall provide
clues regarding the potential genomic, phenotypic and molecular factors responsible for host-switching, which
may lead to prospective emergence and re-emergence of human CoV outbreaks in the future.

Methods:
The seven known human strains of CoV were analyzed for the host and viral factors responsible for
human outbreaks. The molecular factors responsible for host-susceptibility, virulence and pathogenesis were
reviewed to predict the emergence and re-emergence of additional human CoV strains. CoV spike protein was
evaluated as a potential viral receptor for host switching and the target for pharmaceutical design.

Results:
A review of the factors associated with host-susceptibility, virulence and pathogenesis of seven known
human CoV strains presents significant possibilities for the emergence of new CoV strain(s), leading to more
human outbreaks. Continuous exposure of animals’ handlers to the infected animals, environmental changes,
improper sanitations, non-disposal of the solid waste and resumption of exotic animals markets provides favorable
conditions for “host switching” and the emergence of new and potentially more virulent human CoV
strains. Mutations in target genes (like spike protein), which facilitate the viral entry into the host-cells, provide
a potential “molecular switch” for preferences of new host-receptors, genetic diversity, genetic-recombination
and high virulence. Additionally, the clinical and environmental factors, asymptomatic carriers, the paucity of
efficacious vaccines & therapeutics, inefficient disease management and infection control measures, lack of
public awareness, and effective communication of information about more virulent human-adapted virus isolates
are critical for the emergence of new and virulent SARS-CoV strains with high mortality and varied incubation
period in the near future. Small molecules binding with conserved druggable regions of the CoV spike
proteins may be effective against multiple strains of CoVs.

Conclusions:
High propensity of mutations and “molecular adaptations” in coronaviruses creates the hot spots
and high potential for “host switching”, leading to the emergence of more virulent strains of human CoVs. The
public/global health agencies, medical communities and research scientists should be prepared for the emergence
and re-emergence of new human CoV strain(s) leading to potential disease outbreaks. The inhibitors
binding with conserved druggable regions of spike proteins from multiple strains CoV may have utility as
broad-spectrum antiviral drugs to combat future emergence of CoVs.