SHAPE SELECTIVE DNA MINOR GROOVE LIGANDS
形状选择性 DNA 小沟配体
基本信息
- 批准号:2685031
- 负责人:
- 金额:$ 11.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1994
- 资助国家:美国
- 起止时间:1994-04-01 至 2000-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
This proposal details our systematic approach to the design of new,
sequence selective DNA minor groove binding compounds. Our approach
differs from previous approaches in that we Wi" focus on the role of
ligand shape, especially width, in molecular recognition of the minor
groove of double-stranded DNA. We will address two specific questions:
(a) What role does shape play in the interactions of small molecules
with the minor groove? (b) How can we harness the role of ligand shape
to rationally design ligands with predictable sequence and biochemical
selectivities? Our focus on the role of shape in minor groove molecular
recognition will specifically address the issues of the relative
contribution of shape vis-a-vis hydrogen bonding and electrostatic
contributions to molecular recognition, and the ability of the
conformationally flexible minor groove of DNA to accommodate
differently shaped ligands. As an application of this knowledge, we
will specifically address the issues of sequence recognition and the
ability of specific ligand/DNA complexes to effect DNA-processing
enzymes that make contact with the minor groove, including Human
Immunodeficiency Virus Type 1 (HIV-1) reverse transcriptase. Our long
term goal is to have at hand a relatively small number of individual
molecular building blocks, each of which possesses a well defined DNA
binding specificity. These rigid molecular building blocks can then be
assembled in a rational order to construct a DNA minor groove ligand
that complements not only the electrostatic and hydrogen bonding
environment of a particular sequence of DNA, but also its specific
three-dimensional shape. We term such shape complementary DNA minor
groove binding compounds morpholexins, because they read not only the
lexis or "words" of the genetic code but also the morph or "shapes" of
the regions in which these words reside. Specific aims of this work
include:
1. The design and synthesis of two new classes of morpholexin units.
Structural features of the ligands that will be addressed are: the
width, the conformational flexibility, and the hydrogen bonding and
electrostatic functionality.
2. The design and synthesis of linked morpholexins. These compounds
will be designed to probe two specific linking motifs: a head-to-tail
amide bond linker and a head-to-head alkynyldiol linker.
3. The evaluation of the DNA binding of these morpholexins. Two
specific binding characteristics will be investigated: the sequence
selectivity, and the relationship between the minor groove width and
flexibility, and binding site selectivity.
4. The evaluation of the effect of these morpholexins on the DNA-
directed DNA polymerization reaction catalyzed by HIV-1 reverse
transcriptase. Specific investigations will focus on the correlation
of particular DNA binding sites with specific effects of the resulting
ligand/DNA complex on the strand displacement DNA synthesis catalyzed
by HIV-1 reverse transcriptase.
该提案详细介绍了我们设计新,
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SEAN M KERWIN其他文献
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