Combinations of the First and Next Generations of Human Immunodeficiency Virus (HIV) Fusion Inhibitors Exhibit a Highly Potent Synergistic Effect against Enfuvirtide- Sensitive and -Resistant HIV Type 1 Strains

Pan, Chungen; Cai, Lifeng; Liang, Hong; Qi, Zhi; Jiang, Shibo

doi:10.1128/jvi.00168-09

Cited by 50 publications

(45 citation statements)

References 62 publications

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“…Our results showed that T-20-derived peptides seem less active compared with C34 derivatives with N-TRD. Recently, treatment with two or three fusion inhibitors was reported to have a potent and syn-ergistic antiviral activity on T-20-resistant variants (48,49). Together, these observations indicated that each inhibitor has a distinct inhibitory mechanism that may lead to the design of a combination therapy of fusion inhibitors in vivo.…”

Section: Table 3 Antiviral Activity Of Fusion Inhibitors To Sc34-and mentioning

confidence: 94%

Resistance Profiles of Novel Electrostatically Constrained HIV-1 Fusion Inhibitors

Shimura

Nameki

Kajiwara

et al. 2010

Journal of Biological Chemistry

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Human immunodeficiency virus (HIV) gp41 plays a key role in viral fusion; the N-and C-terminal heptad repeats (N-HR and C-HR) of gp41 form a stable 6-helical conformation for fusion. Therefore, HR-derived peptides, such as enfuvirtide (T-20), inhibit HIV-1 fusion by acting as decoys, and have been used for the treatment of HIV-1 infection. However, the efficacy of T-20 is attenuated by resistance mutations in gp41, including V38A and N43D. To suppress the resistant variants, we previously developed electrostatically constrained peptides, SC34 and SC34EK, and showed that both exhibited potent anti-HIV-1 activity against wild-type and T-20-resistant variants. In this study, to clarify the resistance mechanism to this next generation of fusion inhibitors, we selected variants with resistance to SC34 and SC34EK in vitro. The resistant variants had multiple mutations in gp41. All of these mutations individually caused less than 6-fold resistance to SC34 and SC34EK, indicating that there is a significant genetic barrier for high-level resistance. Cross-resistance to SC34 and SC34EK was reduced by a simple difference in the polarity of two intramolecular electrostatic pairs. Furthermore, the selected mutations enhanced the physicochemical interactions with N-HR variants and restored activities of the parental peptide, C34, even to resistant variants. These results demonstrate that our approach of designing gp41-binding inhibitors using electrostatic constraints and information derived from resistance studies produces inhibitors with enhanced activity, high genetic barrier, and distinct resistance profile from T-20 and other inhibitors. Hence, this is a promising approach for the design of future generation peptide fusion inhibitors.

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Section: Table 3 Antiviral Activity Of Fusion Inhibitors To Sc34-and mentioning

confidence: 94%

Resistance Profiles of Novel Electrostatically Constrained HIV-1 Fusion Inhibitors

Shimura

Nameki

Kajiwara

et al. 2010

Journal of Biological Chemistry

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“…Based on our results, the combinational application of HIV-1 fusion inhibitors targeting different sites in NHR, such as CP32M and T20, which mainly target the C-terminal pocket region and the N-terminal GIV motif in the gp41 NHR domain, respectively, is expected to have a synergistic anti-HIV-1 effect, especially against the drug-resistant viral strains, since our previous studies demonstrated this effect when the first-and-next generation HIV fusion inhibitors were combined (31,33). Similarly, a longer peptide containing all the functional domains in CHR may be effective against viruses with mutations resistant to both CP32M and T20.…”

mentioning

confidence: 99%

Mutations of Gln64 in the HIV-1 gp41 N-Terminal Heptad Repeat Render Viruses Resistant to Peptide HIV Fusion Inhibitors Targeting the gp41 Pocket

Cai

et al. 2012

J Virol

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To prove that the peptidic HIV-1 fusion inhibitors containing the pocket-binding domain (PBD) mainly target the hydrophobic pocket in the gp41 N-terminal heptad repeat (NHR), we constructed pseudoviruses by replacement of Q64 in the gp41 pocket region with Ala (Q64A) or Leu (Q64L). These viruses were highly resistant to C34 and CP32M containing the PBD, while they were susceptible to T20 (enfuvirtide) lacking the PBD but containing the GIV-motif-binding domain (GBD) and lipid-binding domain (LBD). They were also sensitive to C52L, which contains the PBD, GBD, and LBD. Those mutations may disrupt the hydrophilic interaction between Q64 in the NHR and N113 in the peptides containing the PBD. This report provides insights into the mechanisms of drug resistance, with implications for the design of novel HIV fusion and entry inhibitors.

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“…For example, combination of enfuvirtide (T20), which binds to the N-terminal region of NHR (containing the GIV motif) but lacks the pocket-binding domain, with sifuvirtide or T1144 (both contain the pocket-binding domain) resulted in strong synergistic antiviral activity against a broad spectrum of HIV-1 strains, especially those resistant to T20 [92,93]. Based on this result, we designed a chimera peptide consisting of T20, a 35-mer linker and T1144, designed TLT35, which showed high potency against HIV-1 gp41-mediated cell-cell fusion and HIV-1 infection [94].…”

Section: Synergistic Combinations Of Multiple Hiv Entry Inhibitorsmentioning

confidence: 99%

Approaches for Identification of HIV-1 Entry Inhibitors Targeting gp41 Pocket

et al. 2013

Viruses

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The hydrophobic pocket in the HIV-1 gp41 N-terminal heptad repeat (NHR) domain plays an important role in viral fusion and entry into the host cell, and serves as an attractive target for development of HIV-1 fusion/entry inhibitors. The peptide anti-HIV drug targeting gp41 NHR, T-20 (generic name: enfuvirtide; brand name: Fuzeon), was approved by the U.S. FDA in 2003 as the first HIV fusion/entry inhibitor for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, because T20 lacks the pocket-binding domain (PBD), it exhibits low anti-HIV-1 activity and short half-life. Therefore, several next-generation HIV fusion inhibitory peptides with PBD have been developed. They possess longer half-life and more potent antiviral activity against a broad spectrum of HIV-1 strains, including the T-20-resistant variants. Nonetheless, the clinical application of these peptides is still limited by the lack of oral availability and the high cost of production. Thus, development of small molecule compounds targeting the gp41 pocket with oral availability has been promoted. This review describes the main approaches for identification of HIV fusion/entry inhibitors targeting the gp41 pocket and summarizes the latest progress in developing these inhibitors as a new class of anti-HIV drugs.

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Combinations of the First and Next Generations of Human Immunodeficiency Virus (HIV) Fusion Inhibitors Exhibit a Highly Potent Synergistic Effect against Enfuvirtide- Sensitive and -Resistant HIV Type 1 Strains

Cited by 50 publications

References 62 publications

Resistance Profiles of Novel Electrostatically Constrained HIV-1 Fusion Inhibitors

Resistance Profiles of Novel Electrostatically Constrained HIV-1 Fusion Inhibitors

Mutations of Gln64 in the HIV-1 gp41 N-Terminal Heptad Repeat Render Viruses Resistant to Peptide HIV Fusion Inhibitors Targeting the gp41 Pocket

Approaches for Identification of HIV-1 Entry Inhibitors Targeting gp41 Pocket

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