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Fejerlectin, a Lectin-like Peptide from the Skin of Fejervarya limnocharis, Inhibits HIV-1 Entry by Targeting Gp41.

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) is mainly transmitted by sexual intercourse, and effective microbicides preventing HIV-1 transmission are still required. Amphibian skin is a rich source of defense peptides with antiviral activity. Here, we characterized a lectin-like peptide, fejerlectin (RLCYMVLPCP), isolated from the skin of the frog Fejervarya limnocharis. Fejerlectin showed significant hemagglutination and d-(+)-galacturonic acid-binding activities. Furthermore, fejerlectin suppressed the early entry of HIV-1 into target cells by binding to the N-terminal heptad repeat of HIV-1 gp41 and preventing 6-HB formation and Env-mediated membrane fusion. Fejerlectin is the smallest lectin-like peptide identified to date and represents a new and promising platform for anti-HIV-1 drug development.

SUBMITTER: Xiong W

PROVIDER: S-EPMC7948434 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Fejerlectin, a Lectin-like Peptide from the Skin of <i>Fejervarya limnocharis</i>, Inhibits HIV-1 Entry by Targeting Gp41.

Xiong Weichen W Zhou Chenliang C Yin Shuwen S Chai Jinwei J Zeng Baishuang B Wu Jiena J Li Yibin Y Li Lin L Xu Xueqing X

ACS omega 20210224 9

Human immunodeficiency virus type 1 (HIV-1) is mainly transmitted by sexual intercourse, and effective microbicides preventing HIV-1 transmission are still required. Amphibian skin is a rich source of defense peptides with antiviral activity. Here, we characterized a lectin-like peptide, fejerlectin (RLCYMVLPCP), isolated from the skin of the frog <i>Fejervarya limnocharis</i>. Fejerlectin showed significant hemagglutination and d-(+)-galacturonic acid-binding activities. Furthermore, fejerlecti ...[more]

PMID: 33718732

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Project description:UnlabelledThe deep hydrophobic pocket on the N trimer of HIV-1 gp41 has been considered an ideal drug target. On the basis of the M-T hook structure, we recently developed short-peptide-based HIV-1 fusion inhibitors (MTSC22 and HP23), which mainly target the pocket site and possess highly potent antiviral activity. In this study, we focused on investigating their resistance pathways and mechanisms by escape HIV-1 mutants to SC22EK, a template peptide for MTSC22 and HP23. Two substitutions, E49K and N126K, located, respectively, at the N- and C-heptad repeat regions of gp41, were identified as conferring high resistance to the inhibitors targeting the pocket and cross-resistance to enfuvirtide (T20) and sifuvirtide (SFT). The underlying mechanisms of SC22EK-induced resistance include the following: (i) significantly reduced binding affinity of the inhibitors, (ii) dramatically enhanced interaction of the viral six-helix bundle, and (iii)severely damaged functionality of the viral Env complex. Our data have provided important information for the structure-function relationship of gp41 and the structure-activity relationship of viral fusion inhibitors.ImportanceEnfuvirtide (T20) is the only HIV-1 fusion inhibitor in clinical use, but the problem of resistance significantly limits its use, calling for new strategies or concepts to develop next-generation drugs. On the basis of the M-T hook structure, short-peptide HIV-1 fusion inhibitors specifically targeting the gp41 pocket site exhibit high binding and antiviral activities. Here, we investigated the molecular pathway of HIV-1 resistance to the short inhibitors by selecting and mapping the escape mutants. The key substitutions for resistance and the underlying mechanisms have been finely characterized. The data provide important information for the structure-function relationship of gp41 and its inhibitors and will definitely help our future development of novel drugs that block gp41-dependent fusion.

Dataset Information

Fejerlectin, a Lectin-like Peptide from the Skin of Fejervarya limnocharis, Inhibits HIV-1 Entry by Targeting Gp41.

Publications

Fejerlectin, a Lectin-like Peptide from the Skin of <i>Fejervarya limnocharis</i>, Inhibits HIV-1 Entry by Targeting Gp41.

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