International Research Fellowship Program: New Chemical Approaches to Glycopeptide Assembly with Application to the Development of New Antigen Motifs for Vaccine Therapy in HIV

国际研究奖学金计划使美国科学家和工程师能够在国外进行三到二十四个月的研究。该计划的奖项提供了联合研究的机会，并利用国外独特或互补的设施、专业知识和实验条件。该奖项将支持萨拉·E·塔利博士与英国牛津大学的波林·M·陆克文博士合作的为期22个月的研究奖学金。大多数成功的疫苗利用中和抗体的力量来产生它们的效果。人类免疫缺陷病毒1型(HIV-1)疫苗的开发一直受到阻碍，因为包膜蛋白碳水化合物能够保护多肽骨架免受抗体识别。最近，人类抗体2G12，一种中和多种HIV-1分离株的抗体，被发现识别包膜蛋白上的一簇碳水化合物部分。类似于2G12抗体的糖蛋白库的产生将使开发针对HIV-1疫苗配方的不同抗体成为可能。为了建立这样一个文库，PI和她的宿主正在开发一种聚合式合成方法来生产N-连接的糖蛋白。他们的方法将具有广泛的实用价值，例如来自化学合成或来自纯化的糖蛋白水解物的葡聚糖可以在没有保护基团的情况下连接到水中的合成多肽序列上，从而建立存在于N-连接的糖蛋白中的正确的b-天冬氨酰胺键。然后，他们将通过构建一个糖蛋白文库来探索其合成方法的实用性，该糖蛋白文库在空间分辨的基因座上表达两个富含甘露糖的糖链结构，作为2G12表位的模型，并作为产生具有类似活性的抗体的抗原。陆克文的实验室已经与糖生物学领域的一些最好的实验室建立了许多国际研究合作。

0502139TullyThe International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-two-month research fellowship by Dr. Sarah E. Tully to work with Dr. Pauline M. Rudd at Oxford University in the United Kingdom.Most successful vaccines utilize the power of neutralizing antibodies to elicit their effects. Development of such a vaccine for human immunodeficiency virus type 1 (HIV-1) has been hampered due to the ability of envelope protein carbohydrates to protect the peptide backbone from antibody recognition. Recently, human antibody 2G12, an antibody that neutralizes a broad range of HIV-1 isolates, was found to recognize a cluster of carbohydrate moieties on the envelope protein. Generation of a library of glycoproteins similar to the 2G12 antibody would enable the development of different antibodies for HIV-1 vaccine formulations. To create such a library, the PI and her host are developing a convergent synthetic approach for the production of N-linked glycoproteins. Their methodology will have broad-based utility such that glycans, derived from chemical synthesis or from purified glycoprotein hydrolysates, can be attached without protecting groups to a synthetic peptide sequence in water with establishment of the correct b-aspartyl amide linkage present in N-linked glycoproteins. They will then explore the utility of their synthetic approach by constructing a glycoprotein library expressing two mannose-rich glycan structures in spatially-resolved loci as a model for the epitope of 2G12 and as an antigen for the generation of anibodies with similar activity.Dr. Rudd's laboratory has established numerous international research collaborations with some of the best laboratories in glycobiology.