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Cloaked similarity between HIV-1 and SARS-CoV suggests an anti-SARS strategy.

Kliger Y, Levanon EY - BMC Microbiol. (2003)

Bottom Line: Recently the FDA approved Enfuvirtide, a synthetic peptide corresponding to the C-terminal heptad repeat of HIV-1 gp41, as an anti-AIDS agent.Enfuvirtide and C34, another anti HIV-1 peptide, exert their inhibitory activity by binding to a leucine/isoleucine zipper-like sequence in gp41, thus inhibiting a conformational change of gp41 required for its activation.We suggest that peptides corresponding to the C-terminal heptad repeat of the S2 protein may serve as inhibitors for SARS-CoV entry.

View Article: PubMed Central - HTML - PubMed

Affiliation: Compugen LTD, Tel Aviv, 69512, Israel. kliger@compugen.co.il

ABSTRACT

Background: Severe acute respiratory syndrome (SARS) is a febrile respiratory illness. The disease has been etiologically linked to a novel coronavirus that has been named the SARS-associated coronavirus (SARS-CoV), whose genome was recently sequenced. Since it is a member of the Coronaviridae, its spike protein (S2) is believed to play a central role in viral entry by facilitating fusion between the viral and host cell membranes. The protein responsible for viral-induced membrane fusion of HIV-1 (gp41) differs in length, and has no sequence homology with S2.

Results: Sequence analysis reveals that the two viral proteins share the sequence motifs that construct their active conformation. These include (1) an N-terminal leucine/isoleucine zipper-like sequence, and (2) a C-terminal heptad repeat located upstream of (3) an aromatic residue-rich region juxtaposed to the (4) transmembrane segment.

Conclusions: This study points to a similar mode of action for the two viral proteins, suggesting that anti-viral strategy that targets the viral-induced membrane fusion step can be adopted from HIV-1 to SARS-CoV. Recently the FDA approved Enfuvirtide, a synthetic peptide corresponding to the C-terminal heptad repeat of HIV-1 gp41, as an anti-AIDS agent. Enfuvirtide and C34, another anti HIV-1 peptide, exert their inhibitory activity by binding to a leucine/isoleucine zipper-like sequence in gp41, thus inhibiting a conformational change of gp41 required for its activation. We suggest that peptides corresponding to the C-terminal heptad repeat of the S2 protein may serve as inhibitors for SARS-CoV entry.

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Related in: MedlinePlus

Wheel projection of the N-HR (a) and C-HR (b) of HIV-1 gp41 (gi/9629363). The amino acid sequence is displayed end-to-end down the axis of a schematic helix. The angle between every two consecutive amino acids is 102.9°. The helical wheel consists of seven corners, corresponding to the fit of seven amino acid residues into every two helical turns.
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Figure 1: Wheel projection of the N-HR (a) and C-HR (b) of HIV-1 gp41 (gi/9629363). The amino acid sequence is displayed end-to-end down the axis of a schematic helix. The angle between every two consecutive amino acids is 102.9°. The helical wheel consists of seven corners, corresponding to the fit of seven amino acid residues into every two helical turns.

Mentions: HIV-1 gp41, which is a well-characterized protein [1,2] contains two heptad repeat (HR) regions, a leucine/isoleucine HR adjacent to its N-terminus (N-HR), and C-HR proximal to the transmembrane domain (see Figure 1). Heptad repeats are characterized by hydrophobic amino acids in the "a" and "d" positions of the helix. In the N-HR of gp41, all but one of the "a" positions are Leucines or Isoleucines. This feature is less strict in the "d" positions of N-HR, and in the "a" and "d" positions of the C-HR. Peptides corresponding to these heptad repeat regions form the "trimer-of-hairpins" core structure of gp41 [3] as confirmed by the solution of the crystal structures [1,2]. Two Cysteine residues and one Proline residue, located between these two HRs, confine a hairpin conformation (Figure 2a). A tryptophan-rich motif, located between the C-HR and the transmembrane domain, was shown to play a crucial role in gp41-mediated membrane fusion [4] (Figure 2a).


Cloaked similarity between HIV-1 and SARS-CoV suggests an anti-SARS strategy.

Kliger Y, Levanon EY - BMC Microbiol. (2003)

Wheel projection of the N-HR (a) and C-HR (b) of HIV-1 gp41 (gi/9629363). The amino acid sequence is displayed end-to-end down the axis of a schematic helix. The angle between every two consecutive amino acids is 102.9°. The helical wheel consists of seven corners, corresponding to the fit of seven amino acid residues into every two helical turns.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC222911&req=5

Figure 1: Wheel projection of the N-HR (a) and C-HR (b) of HIV-1 gp41 (gi/9629363). The amino acid sequence is displayed end-to-end down the axis of a schematic helix. The angle between every two consecutive amino acids is 102.9°. The helical wheel consists of seven corners, corresponding to the fit of seven amino acid residues into every two helical turns.
Mentions: HIV-1 gp41, which is a well-characterized protein [1,2] contains two heptad repeat (HR) regions, a leucine/isoleucine HR adjacent to its N-terminus (N-HR), and C-HR proximal to the transmembrane domain (see Figure 1). Heptad repeats are characterized by hydrophobic amino acids in the "a" and "d" positions of the helix. In the N-HR of gp41, all but one of the "a" positions are Leucines or Isoleucines. This feature is less strict in the "d" positions of N-HR, and in the "a" and "d" positions of the C-HR. Peptides corresponding to these heptad repeat regions form the "trimer-of-hairpins" core structure of gp41 [3] as confirmed by the solution of the crystal structures [1,2]. Two Cysteine residues and one Proline residue, located between these two HRs, confine a hairpin conformation (Figure 2a). A tryptophan-rich motif, located between the C-HR and the transmembrane domain, was shown to play a crucial role in gp41-mediated membrane fusion [4] (Figure 2a).

Bottom Line: Recently the FDA approved Enfuvirtide, a synthetic peptide corresponding to the C-terminal heptad repeat of HIV-1 gp41, as an anti-AIDS agent.Enfuvirtide and C34, another anti HIV-1 peptide, exert their inhibitory activity by binding to a leucine/isoleucine zipper-like sequence in gp41, thus inhibiting a conformational change of gp41 required for its activation.We suggest that peptides corresponding to the C-terminal heptad repeat of the S2 protein may serve as inhibitors for SARS-CoV entry.

View Article: PubMed Central - HTML - PubMed

Affiliation: Compugen LTD, Tel Aviv, 69512, Israel. kliger@compugen.co.il

ABSTRACT

Background: Severe acute respiratory syndrome (SARS) is a febrile respiratory illness. The disease has been etiologically linked to a novel coronavirus that has been named the SARS-associated coronavirus (SARS-CoV), whose genome was recently sequenced. Since it is a member of the Coronaviridae, its spike protein (S2) is believed to play a central role in viral entry by facilitating fusion between the viral and host cell membranes. The protein responsible for viral-induced membrane fusion of HIV-1 (gp41) differs in length, and has no sequence homology with S2.

Results: Sequence analysis reveals that the two viral proteins share the sequence motifs that construct their active conformation. These include (1) an N-terminal leucine/isoleucine zipper-like sequence, and (2) a C-terminal heptad repeat located upstream of (3) an aromatic residue-rich region juxtaposed to the (4) transmembrane segment.

Conclusions: This study points to a similar mode of action for the two viral proteins, suggesting that anti-viral strategy that targets the viral-induced membrane fusion step can be adopted from HIV-1 to SARS-CoV. Recently the FDA approved Enfuvirtide, a synthetic peptide corresponding to the C-terminal heptad repeat of HIV-1 gp41, as an anti-AIDS agent. Enfuvirtide and C34, another anti HIV-1 peptide, exert their inhibitory activity by binding to a leucine/isoleucine zipper-like sequence in gp41, thus inhibiting a conformational change of gp41 required for its activation. We suggest that peptides corresponding to the C-terminal heptad repeat of the S2 protein may serve as inhibitors for SARS-CoV entry.

Show MeSH
Related in: MedlinePlus