2009 Drug Targets in Severe Acute Respiratory Syndrome (SARS) Virus and other Coronavirus Infections

23 Pages·2009·0.81 MB·English

Infectious Disorders - Drug Targets 2009, 9, 223-245
223

1871-5265/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Drug Targets in Severe Acute Respiratory Syndrome (SARS) Virus and
other Coronavirus Infections

Tommy R. Tong*

Department of Pathology, Montefiore Medical Center, Bronx, NY

Abstract: Coronaviruses are important human and animal pathogens of the order Nidovirales. Several new members were
discovered following the emergence of SARS-CoV in human populations, including two human coronaviruses and several
animal coronaviruses. They cause respiratory and gastrointestinal illnesses and have been found in the brains of patients
with multiple sclerosis. The high mortality of SARS, the identification of a natural reservoir, and the well-founded fear of
provoking antibody-enhanced disease as a result of vaccination fueled the ongoing efforts in anti-coronavirus drug
discovery. This review presents the results of current research.

Keywords: Coronavirus, SARS-CoV, Severe acute respiratory syndrome, SARS, main protease, 3CLpro, polymerase, helicase,
interferon, interferon-inducer, antibody

INTRODUCTION

The coronaviruses, together with the arteriviruses, belong
to the order Nidovirales, by virtue of sharing the trans-
criptome of a nested set of subgenomic mRNAs [1]. They
are enveloped positive-sense single-stranded RNA viruses
(Baltimore group IV). The coronaviruses have the largest
genome (around 30K) among the RNA viruses. They infect
humans, mammals and birds. Phylogenetically, the coro-
naviruses can be divided into three subgroups, two of which
are mammalian (groups 1 and 2) and the remaining avian
(group 3). This corresponds to the serotype classification.
The previously well-studied human coronaviruses (HCoV), -
OC43 and -229E, and the novel HCoV-NL63 and -HKU1,
and SARS-CoV, are found in groups 1 and 2, along with
various other mammalian coronaviruses. The recently
discovered SARS-CoV belongs to subgroup 2b, along with
bat-CoV, the putative ancestor [2-5], There is evidence that
H-CoV-OC43 is also a zoonosis, probably arising from
bovine CoV [6].

Diseases caused by the generally epitheliotropic viruses
include respiratory and gastrointestinal illnesses. However,
neurotropism is demonstrated in brains of patients suffering
from multiple sclerosis [7, 8]. Other tissues may also be
susceptible, as seen in SARS [9, 10].

Severe acute respiratory syndrome (SARS), caused by
SARS-CoV [11-16], emerged in late 2002 in southern China,
spreading to 29 countries within a few weeks, and infected
~8,000 people resulting in close to 800 deaths. It is a
pneumonia with 10% fatality rate [11, 12, 17-19] and
pathogenesis encompassing viral infection of pneumocytes
in the lower respiratory tract [20-23], disturbance of the
rennin-angiotensin system [24-29] and alterations in the
innate [30] and adaptive immune systems [31]. After the
epidemic, the natural reservoir was identified, the viral life

*Address correspondence to this author at the Department of Pathology,
Jack D. Weiler Hospital, 1825 Eastchester Road, Bronx, NY 10461; Tel:
661-889-8218; Fax: [phone]; E-mail: