Although the 21st century has brought incredible modern advancements in both technology and medicine, we still have a long way to go in eliminating the world's most dangerous parasitic diseases. For those in the Global North, the risk and severity of these deadly infections is fairly removed - although even that is not an absolute. This is largely due to the established infrastructure that provides adequate sanitation facilities, as well as living conditions that allow for those that are infected to access the necessary healthcare quickly enough to receive treatment.
In contrast, for those in the Global South, the lack of infrastructure and access to healthcare, as well as the ever-growing disparity of wealth, means that - even in 2023 - these diseases are a very real threat. In fact, according to the CDC, malaria is the most deadly parasitic disease and it kills more than 400,000 people each year. The vast majority of those deaths are impoverished young children, who are by far the most vulnerable.
Who is Dr. Suraksha Gahalawat?
Dr. Suraksha Gahalawat was born and raised in India, and has seen firsthand the devastation that these illnesses can cause in developing nations. With a passion for organic chemistry, she completed her Master of Science degree in 2012 from India's Kurukshetra University and was amongst the top 10 of her graduating class. From there, she went on to complete her PhD in 2017 at the Thapar Institute of Engineering and Technology (formerly Thapar University).
After completing her studies, Dr. Suraksha's efforts earned her the opportunity to join the incredible team of Professor Joseph Martin Ready at the University of Texas Southwestern Medical Center, where she has been working as a postdoctoral researcher since 2018. She is esteemed as both a medicinal and synthetic chemist. Primarily, her research has focused on the design, synthesis and characterization of small, biologically active molecules for the development of novel therapeutics to treat infectious diseases. In her own words, she explains: "I am well accustomed to the development, synthesis, and optimization of synthetic methodologies to solve challenging chemical transformations that could streamline bioactive molecular development."
Dr. Suraksha is an extremely valuable member of the team because she offers a unique perspective, with a diverse background in organic chemistry, medicinal chemistry and chemical biology. This provides her with a strong understanding of how to work with a drug target and mechanism to create a healing solution and treatment.
Malaria
This parasitic disease has been at the forefront of medicinal research for nearly a century. There have been various drugs used to treat malaria, such as chloroquine (CQ), sulfadoxine, and pyrimethamine. However, with each new drug, this parasite mutates and manages to develop even more powerful resistance - bringing scientists back to the drawing board to develop a new and effective treatment program.
According to the Journal of Medicinal Chemistry, "The causative agent of malaria is an obligate intracellular parasite from the Plasmodium genus, of which there are five human infective species. Plasmodium falciparum and Plasmodium vivax account for most cases of malaria, with the former responsible for almost all malaria deaths."
In hopes of identifying new antimalarials, Dr. Suraksha, along with the UT Southwestern Medical Center team, conducted a phenotypic screening and identified a novel tetrazole-based series that not only demonstrated fast-kill kinetics, but also showed a relatively low propensity to develop high-level resistance. Dr. Suraksha's research team then decided to test whether the series had a similar mechanism of action to CQ, and the results revealed a pattern of intracellular inhibition of hemozoin (Hz) formation that was indeed reminiscent of CQ's action. She explains: "We identified a novel chemical series that targets the historically druggable heme polymerization pathway, and that can form the basis of future optimization efforts to develop a new malaria treatment."
Leishmaniasis
Leishmaniasis is another parasitic disease with massive global impact. It is lesser known than malaria - in fact, it is on the WHO's list of Neglected Tropical Diseases (NTDs) - but it is endemic in nearly 100 countries. It is transmitted by the bite of infected female phlebotomine sandflies, with somewhere between 700,000 and 1M new cases occurring annually.
The disease takes three different forms in humans. The first is visceral, affecting internal organs, such as the spleen and liver, which is the most serious as it is almost always fatal without immediate diagnosis and treatment. The second is cutaneous, the most common form, which causes skin ulcers and lesions. The last is mucocutaneous, which affects the mucous membranes of the mouth, nose, and throat. Sadly, there are very few antileishmanial drugs and each one has significant side effects. Similarly to antimalarials, resistance has also emerged, and the reality is that effective vaccines are likely to be decades away. There is urgency to find a better solution.
Thankfully, Dr. Suraksha's team at UT Southwestern Medical Center has made significant strides. In hopes of developing new drugs for this neglected tropical disease, they tested the activity of compounds in the Medicines for Malaria Venture (MMV) "Pathogen Box" against Leishmania amazonensis axenic amastigotes. Through their research, Dr. Suraksha's team identified and validated a hit compound, MMV676477, which also kills other protozoan parasites: Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. They demonstrated that this compound is a potent antiparasitic compound that preferentially promotes Leishmania microtubule polymerization. Furthermore, due to its selectivity for and broad-spectrum activity against multiple parasites, this scaffold shows promise for antiparasitic drug development.
In conclusion
Dr. Suraksha Gahalawat brings an immense depth of knowledge and enthusiasm to the world of biopharmaceuticals. Although she has only been working professionally for about five years, her contributions to UTSW's research and drug development projects have been significant. Their work was actually patented in April 2021 - an impressive mark for such a young scientist.
In conclusion, Dr. Suraksha explains: "The drugs for leishmaniasis target parasite tubulin polymerization, and the drugs for malaria target the historically druggable heme polymerization pathway. [These discoveries] will allow for the development of compounds with a high therapeutic index for the treatment of trypanosomatid infections and malaria illnesses. Specifically, my effort is geared towards the utilization of chemical derivatization and forward genetic approaches to study a class of compounds that selectively test activity on leishmania tubulin, trypanosomatids and malaria heme polymerization, assess their stability, solubility, cell permeability, and in vivo PK properties."
While she currently performs proof-of-concept testing in animal models, Dr. Suraksha's team is making amazing progress. Their work leaves us feeling hopeful that effective drug treatments for these devastating diseases may actually be just around the corner, and that's exactly what keeps Dr. Suraksha motivated and focused.
