巰基烯能製備S脂質化抗HBV肽

StephenW

Thiol-ene enabled preparation of S-lipidated anti-HBV peptides
Oscar A Shepperson  1 , Alan J Cameron  1 , Carol J Wang  2 , Paul W R Harris  1 , John A Taylor  3 , Margaret A Brimble  1
Affiliations
Affiliations

    1
    School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland 1010, New Zealand and School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand and Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand. [email protected] [email protected].
    2
    School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand.
    3
    School of Biological Sciences, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand and Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, 3A Symonds St, Auckland 1010, New Zealand. [email protected] [email protected].

    PMID: 33185215 DOI: 10.1039/d0ob01997f

Abstract

Despite significant efforts made towards treatments for Hepatitis B virus (HBV), a long-term curative treatment has thus far eluded scientists. Recently, the Sodium Taurocholate Co-Transporting Polypeptide (NTCP) receptor has been identified as the entry pathway of HBV into hepatocytes. Myrcludex B, an N-terminally myristoylated 47-mer peptide mimic of the preS1 domain of the Hepatitis B virion, was identified as a potent protein-protein interaction (PPI) inhibitor blocking HBV fusion (IC50 = 140 pM). Herein we report an optimised chemical synthesis of Myrcludex B and a series of novel analogues. Employing a small modification to the Cysteine Lipidation of a Peptide or Amino acid (CLipPA) thiol-ene reaction, a library of S-lipidated Myrcludex B and truncated (21-mer) analogues were prepared, providing novel chemical space to probe for the discovery of novel anti-HBV peptides. The S-lipidated analogues showed an equivalent or a slight decrease (∼2-fold) in binding effectiveness to NTCP expressing hepatocytes compared to Myrcludex B. Three S-lipidated analogues were highly potent HBV inhibitors (IC50 0.97-3.32 nM). These results demonstrate that incorporation of heteroatoms into the lipid 'anchor' is tolerated by this antiviral scaffold and to the best of our knowledge constitutes the first report of potent S-lipidated antiviral peptides. Interestingly, despite only moderate reductions in binding effectiveness, truncated analogues possessed dramatically reduced inhibitory activity thus providing new insights into the structure activity relationship of these hitherto unreported antiviral S-lipopeptides.

StephenW

巰基烯能製備S脂質化抗HBV肽
奧斯卡謝潑德1，艾倫·卡梅倫1，卡羅爾·王2，保羅·W·哈里斯1，約翰·泰勒3，瑪格麗特·布里姆布爾1
隸屬關係
隸屬關係

    1個
    奧克蘭大學化學科學學院，新西蘭西10奧克蘭1010，奧克蘭大學生物科學學院，奧克蘭1010新西蘭西蒙3 St，奧克蘭1010，新西蘭大學莫里斯·威爾金斯分子生物發現中心奧克蘭，3A Symonds St，奧克蘭1010，新西蘭。 [email protected] [email protected]。
    2
    奧克蘭大學生物科學學院，奧克蘭西路1010號Symonds St，3A，新西蘭。
    3
    奧克蘭大學生物科學學院，新西蘭奧克蘭1010 Symonds St，3A和奧克蘭大學莫里斯·威爾金斯分子生物發現中心，新西蘭奧克蘭1010 Symonds St 3A。 [email protected] [email protected]。

    PMID：33185215 DOI：10.1039 / d0ob01997f

抽象

儘管為治療乙型肝炎病毒（HBV）做出了巨大努力，但迄今為止，長期的治療方法還沒有引起科學家的重視。最近，牛磺膽酸鈉共轉運多肽（NTCP）受體已被確定為HBV進入肝細胞的進入途徑。 Myrcludex B是乙型肝炎病毒粒子preS1結構域的N端肉荳蔻酰化的47-mer肽模擬物，被認為是一種有效的蛋白-蛋白相互作用（PPI）抑製劑，可阻斷HBV融合（IC50 = 140 pM）。在本文中，我們報告了Myrcludex B和一系列新型類似物的優化化學合成。通過對肽或氨基酸（CLipPA）硫醇-烯反應的半胱氨酸脂質進行小的修飾，製備了S-脂質Myrcludex B和截短的（21-mer）類似物的文庫，為探索該發現提供了新的化學空間新型抗HBV肽與Myrcludex B相比，S脂質類似物對錶達NTCP的肝細胞的結合效力表現出相同或輕微的下降（約2倍）。三種S脂質類似物是高效的HBV抑製劑（IC50為0.97-3.32 nM）。這些結果表明，該抗病毒支架可耐受將雜原子摻入脂質“錨”中，並且據我們所知，這是有關強S脂質化抗病毒肽的首次報導。有趣的是，儘管結合效力僅適度降低，但截短的類似物具有顯著降低的抑制活性，因此提供了對這些迄今未報導的抗病毒S-脂肽的結構活性關係的新見解。