Dissertation/Thesis Abstract

Halofuginone: A story of how target identification of an ancient Chinese medicine and multi-step evolution informs malaria drug discovery
by Herman, Jonathan David, Ph.D., Harvard University, 2014, 131; 3626689
Abstract (Summary)

Malaria is a treatable communicable disease yet remains a common cause of death and disease especially among pregnant women and children. Most of malaria's worldwide burden disproportionately lies in Southeast Asia and Sub-Saharan Africa. Western medicine's 100+ year history of combating Plasmodium falciparum has taught us that the global population of malaria parasites has a unique and dangerous ability to rapidly evolve and spread drug resistance. Recently it was documented that resistance to the first-line antimalarial artemisinin may be developing in Southeast Asia.

The goal of this work is to develop new targets for antimalarial drug development and use these new tools to better understand the evolutionary process of adaptation to antimalarial drugs. We focused on derivatives of the natural product antimalarial febrifugine. We first identified that febrifugine derivative halofuginone targets the P. falciparum cytoplasmic prolyl tRNA synthetase (cPRS). We then found another febrifugine derivative, halofuginol, which shared halofuginone's mechanism of action but lacked its toxicity in an in vivo murine model of malaria.

By studying the multiple mechanisms that P. falciparum utilizes to evolve resistance to halofuginone, we present a three-step sequential model of the evolution of drug resistance in malaria. In the case of halofuginone, we found non-genetic regulation of the clag family of genes achieved specific increase of proline pools in addition to genetic modification of the cPRS were fundamental in the evolution of resistance.

By focusing on cPRS drug resistance mutations with a reverse genetic approach, we further found evidence that drug resistance mutations can be the second of a two-step evolutionary process. We found that both cPRS mutations L482F (HFGRI) and L482H (HFGRII) required a cellular environment with the overexpression of clag gene family members to confer resistance to halofuginone.

Taken together, these data identify the cPRS as a new and promising target for malaria drug development, halofuginol as a promising chemical scaffold for the development of future cPRS-based antimalarials, and a new model of the evolution of drug resistance involving sequential non-genetic and genetic adaptations.

Indexing (document details)
Advisor: Wirth, Dyann F.
Commitee: Duraisingh, Manoj, Garraway, Levi, Gray, Nathanael, Winzeler, Elizabeth
School: Harvard University
Department: Biology: Medical Sciences, Division of
School Location: United States -- Massachusetts
Source: DAI-B 75/10(E), Dissertation Abstracts International
Subjects: Evolution and Development, Alternative Medicine, Public health, Parasitology
Keywords: Drug resistance, Evolution, Halofuginone, Malaria, Non-genetic adaptation, tRNA synthetase
Publication Number: 3626689
ISBN: 9781321017113