effective drugs for the treatment of human immunodeficiency virus. The dawning of the
21st century has brought new concerns about seemingly new viruses, including SARS
and avian flu. The new century has also brought new concerns about old viruses, such
as the weaponizationof viruses (e.g., smallpox) as tools of bioterrorism and weapons
of mass destruction. These worries are further compounded by the dire predictions of
epidemiologists who foresee the “long overdue” re-emergence of worldwide killer flu
epidemics such as the Spanish flu epidemic of 1918. Although vaccines represent an
effective tool against viruses, vaccines can take a long time to produce and their devel-
opment may be too late to confront a rapidly spreading epidemic. Moreover, not all
viruses are amenable to immunotherapy via vaccines. Clearly, the design of antivirals
is an important, indeed crucial, medicinal chemistry priority. Regrettably, the develop-
ment of antiviral drugs has been (and continues to be) a very slow and frustrating field.
It is not nearly as well advanced as bacterial chemotherapy.
When designing new chemical entities as putative antivirals, there are seven logical
steps in viral biochemistry and replication at which druggable targets suitable for drug
design can be identified:
- Penetration of the virus into the susceptible host cell
(blocked, non-specifically, by γ-globulins) - Uncoating of the viral nucleic acid through shedding of the protein coat
(blocked by amantadine (9.1)) - Synthesis of early regulatory proteins (nucleic acid polymerases) used to aid nucleic
acid synthesis
(blocked by fomivirsen (9.2)) - Synthesis of either RNA or DNA
(blocked by purine or pyrimidine analogs) - Synthesis of late structural proteins so that the nucleic acids can be “re-coated”
(blocked by methimazole (9.3) or protease inhibitors)
550 MEDICINAL CHEMISTRY
Table 9.1 Continued
Family agent Disease
Hepatitis A virus Hepatitis (ususally mild, rarely chronic)
Rhinovirus (over 100 serotypes) Common cold, pneumonia
Reovirus
Human rotavirus Gastroenteritis in infants
Orbivirus Colorado tick fever
Retrovirus
Human immunodeficiency viruses
(HIV-1, HIV-2) T-cell leukemia
Rhabdovirus
Rabies virus Rabies
Togavirus
Alphaviruses Encephalitis, hemorrhagic fevers
Rubivirus Rubella (German measles)