From genome to antivirals: SARS as a test tube - PubMed (original) (raw)

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From genome to antivirals: SARS as a test tube

Yossef Kliger et al. Drug Discov Today. 2005.

Abstract

The severe acute respiratory syndrome (SARS) epidemic brought into the spotlight the need for rapid development of effective anti-viral drugs against newly emerging viruses. Researchers have leveraged the 20-year battle against AIDS into a variety of possible treatments for SARS. Most prominently, based solely on viral genome information, silencers of viral genes, viral-enzyme blockers and viral-entry inhibitors were suggested as potential therapeutic agents for SARS. In particular, inhibitors of viral entry, comprising therapeutic peptides, were based on the recently launched anti-HIV drug enfuvirtide. This could represent one of the most direct routes from genome sequencing to the discovery of antiviral drugs.

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Figures

FIGURE 1

FIGURE 1

The SARS-CoV life cycle is vulnerable to therapeutic intervention in several places. (1) Virus binding to cellular receptors. Outside the cell, blocking the interaction of SARS-CoV with the cellular receptor will prevent the virus from attaching to host cells. Co-receptor antagonists will prevent the initiation of the next step. (2) Membrane fusion of the virion with the host. Fusion inhibitors will block merging of the viral membrane with the host cell membrane. (3) Viral RNA processing. Within the cell, transcription and multiplication of the viral RNA can be blocked by polymerase and helicase inhibitors. Translation of the viral proteins might be inhibited by blocking mRNA capping. (4) Protein maturation. Viral proteins will not mature in the presence of protease inhibitors, rendering them useless.

FIGURE 2

FIGURE 2

Similarity between the fusion proteins of HIV-1 and SARS-CoV. Schematic illustration of (a) HIV-1 gp41 and (b) the equivalent S2 protein from the SARS-CoV. A Leucine/Isoleucine heptad repeat adjacent to the N-terminus of both proteins appears in red. The C-HR is in green. Cysteine residues (purple) confining a loop structure are located between the two heptad repeats. An aromatic residues-rich motif is marked blue, and the transmembrane segment is in orange. A peptide corresponding to the C-HR, which acts as potent inhibitor of HIV-1 entry into the cell, appears in yellow. The helical wheel is a top view of a single strand of a coiled coil. In the wheel projection of the N-HR (c) and C-HR (d) of SARS-CoV S2 protein, each of the seven positions (a-g) corresponds to the location of an amino acid residue that makes up the coiled coil. The arrows between the seven positions indicate the relative locations of adjacent residues in an amino acid subsequence. The helical wheel demonstrates how a potential antiviral drug can be discovered based solely on sequence information.

FIGURE 3

FIGURE 3

A time line comparing key achievements in AIDS and SARS research. Effective international collaborations and technological advances greatly accelerated the understanding of viral diseases. It is anticipated that these research achievements will also lead to faster drug discovery and development.

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