Year: 2017
Type: article
Abstract: The human immunodeficiency virus (HIV-1) is a well-recognized threat to global public health, with current estimates of ~37 million infected individuals worldwide [1]. While efforts to develop an effective vaccine to prevent infection have not come to fruition, several FDA approved drugs targeting HIV-1 have proven effective in reducing viral replication and improving quality of life [2]. Yet, due to the increasing emergence of drug resistant variants, new HIV-1 treatments are needed as the virus continues to evolve. Structure-based drug design is a powerful approach for facilitating the development of new HIV-1 inhibitors [3], driven mainly by x-ray crystallographic studies of viral proteins [4]. However, the static nature of crystallographic studies necessitate complementary structural and dynamic studies to genuinely understand protein-ligand interactions. In this thesis, solution NMR is used to investigate HIV-1 RT, a major therapeutic target in the fight against HIV-1 infection. HIV-1 reverse transcriptase produces viral DNA from genomic RNA and is essential for the viral lifecycle [5]. Although the structure of the mature heterodimer has been well characterized, less is known about RT maturation from its p66 immature precursor, which so far has resisted crystallization. I used NMR to investigate RT maturation and to elucidate RT interactions with FDA approved inhibitors. Together the results of my thesis contribute to arrive at a more comprehensive understanding of RT maturation and RT-inhibitor interactions.
Author: Naima G. Sharaf
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2600202185