Human immunodeficiency virus (HIV) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections. A number of synthetic peptides derived from the N- and C-heptad repeat (NHR and CHR) regions of the HIV-1 envelope glycoprotein (Env) transmembrane subunit gp41 were discovered to have potent anti-HIV activity.

Bokeschab HR et al., in 2004 isolated and characterized anti-HIV peptides from Dorstenia contrajerva and Treculia obovoidea. Using a high throughput screen based on the interaction of the HIV-1 gp41 ectodomain with the virucidal protein cyanovirin-N (CV-N), they isolated two new peptides which inhibited the binding of CV-N to gp41 and which subsequently showed anti-HIV activity in a whole cell assay 1. Shi W et al., in 2008 designed a series of peptides containing the artificial HR (heptad repeat) sequence regions of the HIV-1 envelope glycoprotein (Env). They found that the peptides consisting of coiled-coil structures exhibited inhibitory activity on HIV-1-mediated cell-cell fusion activity, HIV-1 replication, and gp41 6-HB (six-helix bundle) formation, while addition of LBD (lipid-binding domain) and/or PBD (pocket-binding domain) led to a significant increase of the anti-HIV-1 activity 2.  Tachyplesin and polyphemusin are antimicrobial peptides isolated from the hemocytes of horseshoe crabs (Tachypleus tridentatusand Limulus polyphemus). Tamamura H et al., in 1996 synthesized them and their analogs and examined their antiviral activity against human immunodeficiency virus (HIV) and found that [Tyr5,12, Lys7]-polyphemusin II, which was designated as T22, had extremely high anti-HIV activity 3

Structural Characteristics
T22 ([Tyr5, 12, Lys7]-polyphemusin II) is short, positively charged peptide. T22 takes an antiparallel β-sheet structure maintained by two disulfide bridges and contains two antiparallel repeats of Cys-Tyr-Arg-Lys-Cys. As reported herein, fully reduced T22 was found by HPLC and ion spray mass spectrometric analyses to form a complex in a molar ratio of 1:1 with Zn2+ ion at neutral pH in aqueous solution. Complexation of Zn2+ ion to this peptide appears to result in tetracoordinate bonding to sulfur atoms of four Cys residues. They also found that the anti-HIV activity of the T22-Zn2+ complex was fourfold stronger than that of T22 3.  Synthetic peptides derived from the gp41 CHR regions, e.g., T20 (generic name: Enfuvirtide, brand name: Fuzeon) and C34 (Heptad repeat2 region of gp41), share a common HR sequence as a structural domain, but contain different functional domains, i.e., lipid-binding domain (LBD) and pocket-binding domain (PBD), respectively. It is believed that CHR-peptides inhibit HIV fusion by interacting through their HR sequences with the viral gp41 NHR region blocking gp41 6-HB core formation 4.

Mode of Action
During HIV infection, gp120 binds to CD4 and a chemokine receptor (CCR5 or CXCR4) on the target cell to trigger gp41 structural rearrangement. This results in the formation of a stable gp41 six-helix bundle (6-HB) core structure, in which three NHR-helices associate to form the central trimeric coiled coil. Three C-helices pack obliquely in an anti-parallel manner into the highly conserved hydrophobic grooves on the surface of the NHR-trimer. In each groove, there is a highly conserved hydrophobic deep pocket formed by the pocket-forming sequence (residues 565-581) in the NHR region. This pocket plays a critical role in viral fusion and maintaining the stability of the 6-HB. The formation of 6-HB is believed to bring both the viral and target cell membranes into proximity, resulting in fusion between the virus and target cell membranes 5,6.

T22 exerts its effect by blocking virus-cell fusion and that T22 might interact with an HIV envelope protein and/T-cell surface protein. T22 binds specifically to both gp120 (an envelope protein of HIV) and CD4 (a T-cell surface protein) and that both bindings can be inhibited by an anti-T22 antibody 7.


Scytovirin (SVN) is an equally potent anti-HIV protein, isolated from aqueous extracts of the cyanbacterium, Scytonema varium. Low, nanomolar concentrations of SVN have been reported to inactivate laboratory strains and primary isolates of HIV- 1 8

A synthetic polymeric construction (SPC3) containing the consensus sequence of the apex of the V3 domain of HIV. SPC3 was shown to be a potent inhibitor of HIV infection in CD4+ cell cultures even when added 1 h after initial exposure of the cells to HIV 6.

SPC3 is a peptide construct (eight branches of the GPGRAF motif) derived from the consensus sequence present at the apex of the third variable domain of the HIV envelope (Env). It presents a potent anti-HIV activity 8.


1.    Bokesch HR, Charan RD, Meragelman KM, Beutler JA, Gardella R, O'Keefe BR, McKee TC, McMahon JB (2004). Isolation and characterization of anti-HIV peptides from Dorstenia contrajerva and Treculia obovoidea. FEBS letters., 567(2): 287-290.

2.    Shi W, Qi Z, Pan C, Xue N, Debnath AK, Qie J, Jiang S, Liu K (2008). Novel anti-HIV peptides containing multiple copies of artificially designed heptad repeat motifs. Biochem Biophys Res Commun., 374(4):767-772.

3.    Tamamura H, Otaka A, Murakami T, Ibuka T, Sakano K, Waki M, Matsumoto A, Yamamoto N, Fujii N (1996). An Anti-HIV Peptide, T22, Forms a Highly Active Complex with Zn(II). Biochemical and Biophysical Research Communications, 229(2):648-652.

4.    Chan DC, Kim PS (1998). HIV entry and its inhibition. Cell, 93:681-684.

5.    Chan DC, Fass D, Berger JM, Kim PS (1997). Core structure of gp41 from the HIV envelope glycoprotein. Cell, 89:263-273. 

6.    Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC (1997). Atomic structure of the ectodomain from HIV-1 gp41. Nature, 387:426-428.

7.    Tamamura H, Otaka A, Murakami T, Ishihara T, Ibuka T, Waki M, Matsumoto A, Yamamoto N, Fujii N (1996). Interaction of an Anti-HIV Peptide, T22, with GP120 and CD4. Biochemical and Biophysical Research Communications, 219(2):555-559.

8.    Barbouche R, Miquelis R, Sabatier JM, Fenouillet E (1998). SPC3, an Anti-HIV peptide construct derived from the viral envelope, binds and enters HIV Target Cells. J. Peptide Sci., 4:479-485.

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