A θ-defensin composed exclusively of D-amino acids is active against HIV-1
A θ-defensin composed exclusively of D-amino acids is active against HIV-1
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DOI：
10.1111/j.1399-3011.2004.00155.x
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发表时间：
2004-06-01
期刊：
影响因子：
--
通讯作者：
Lal, RB
中科院分区：
文献类型：
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作者：
Owen, SM;Rudolph, D;Lal, RB
某些θ-防御素（包括逆转录细胞周期蛋白-1）保护人类细胞免受HIV-1感染的能力，标志着它们是潜在的有用分子。由L-氨基酸组成的θ-防御素在含有宿主和微生物蛋白酶的环境中可能是不稳定的。本研究比较了两种对映体的θ-防御素，retrocyclin-1和RC-112的性质。虽然这些肽具有相同的序列，但RC-112仅由D-氨基酸组成，而retrocyclin-1仅含有L-氨基酸。我们比较了这些肽保护JC 53-BL人细胞免受30种主要HIV-1分离株感染的能力。JC 53-BL细胞是表达表面CD 4、CXCR 4和CCR 5的修饰的HeLa细胞。它们还含有由HIV-1 LTR驱动的报告盒，并表达β-半乳糖苷酶和荧光素酶。HIV-1分离株的共受体特异性各不相同，包括A、B、C、D、CRF 01-AE和G亚型。在整个HIV-1组中，RC-112的效力是retrocyclin-1的数倍。尽管RC-112结合固定化的gp 120和CD 4的亲和力低于retrocyclin-1，但用1 μ g/mL RC-112和retrocyclin-1进行的表面等离子体共振实验显示，两种糖蛋白的结合程度相似。RC-112的上级抗病毒性能最可能反映了其对JC 53-BL靶细胞的表面相关或分泌蛋白酶降解的抗性。完全由D-氨基酸组成的θ-防御素值得考虑作为设计局部应用于阴道或直肠的杀微生物剂的起点。
The ability of certain theta-defensins, including retrocyclin-1, to protect human cells from infection by HIV-1 marks them as potentially useful molecules. theta-Defensins composed of L-amino acids are likely to be unstable in environments that contain host and microbial proteases. This study compared the properties of two enantiomeric theta-defensins, retrocyclin-1, and RC-112. Although these peptides have identical sequences, RC-112 is composed exclusively of D-amino acids, whereas retrocyclin-1 contains only L-amino acids. We compared the ability of these peptides to protect JC53-BL human cells from infection by 30 primary HIV-1 isolates. JC53-BL cells are modified HeLa cells that express surface CD4, CXCR4, and CCR5. They also contain reporter cassettes that are driven by the HIV-1 LTR, and express beta-galactosidase and luciferase. The HIV-1 isolates varied in co-receptor specificity and included subtypes A, B, C, D, CRF01-AE, and G. RC-112 was several fold more potent than retrocyclin-1 across the entire HIV-1 panel. Although RC-112 bound immobilized gp120 and CD4 with lower affinity than did retrocyclin-1, surface plasmon resonance experiments performed with 1 mug/mL of RC-112 and retrocyclin-1 revealed that both glycoproteins were bound to a similar extent. The superior antiviral performance of RC-112 most likely reflected its resistance to degradation by surface-associated or secreted proteases of the JC53-BL target cells. theta-Defensins composed exclusively of D-amino acids merit consideration as starting points for designing microbicides for topical application to the vagina or rectum.