Novel Molecules Show Promise in Fighting Zika Virus: Research at Hunter College
The Zika virus, notorious for causing microcephaly and other severe brain defects in developing fetuses of infected pregnant women, remains a significant global health concern. With no approved antiviral therapies specifically targeting Zika, the need for effective treatments is urgent. Researchers at the Advanced Science Research Center (ASRC) at The Graduate Center of The City University of New York, Hunter College, and their collaborators at Texas Tech University Health Sciences Center are pursuing a groundbreaking discovery that may lead to a much-needed treatment.
Developing a New Class of Anti-Zika Molecules
Spearheaded by the ASRC's Nanoscience Initiative, the scientists have developed a new class of molecules demonstrating potent anti-Zika activity while exhibiting low toxicity towards animal cells. According to ASRC and Hunter College Chemistry Professor Adam Braunschweig, whose lab is leading the research, "Our molecules are more potent than almost anything currently being used against Zika."
How Viruses and Cells Recognize Each Other
All viruses and eukaryotic cells, including plant and animal cells, possess carbohydrates attached to their surfaces. These carbohydrates function as ID tags, enabling cells to recognize each other through carbohydrate receptors. Viruses exploit this same mechanism to gain entry into cells.
Synthetic Carbohydrate Receptors: A Novel Approach
The researchers created synthetic carbohydrate receptors, subsequently testing their anti-Zika activity in Vero and HeLa cells. In both instances, the molecules displayed remarkable potency. Braunschweig suggests that the receptors likely combat the infection through one of two pathways: either by binding to the carbohydrates on the surfaces of cells or by binding to those of the virus.
Synthetic carbohydrate receptors are typically limited in their utility due to their lack of discrimination in binding. However, in this study, the researchers achieved highly effective receptors by mimicking the binding approach of naturally occurring receptors.
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Potential Mechanism of Action
The study's data demonstrates that these synthetic carbohydrate receptors (SCRs) are highly potent, with IC50 values as low as 0.16 μM and negligible toxicity at concentrations several-fold higher. Time-of-addition studies indicated that these SCRs inhibit the early stages of the virus infection, aligning with the proposed mode of action. The SCRs likely inhibit binding between the virus and cell-surface glycans, thereby preventing viral entry into the cells. This demonstrates a potential new strategy against ZIKV.
Future Directions: Enhancing Effectiveness
A crucial next step in the researchers' quest for an effective Zika treatment involves creating a second generation of molecules. This will be achieved by leveraging the chemical intuition gained from the current study to modify the structures, further enhancing their effectiveness.
Glycan Microarrays: Accelerating Discovery
Spatially encoded glycan microarrays hold immense promise for rapidly accelerating our understanding of glycan binding in various biological processes. This understanding could pave the way for new therapeutics and previously unknown drug targets.
Researchers are utilizing a digital micromirror device, microfluidic introduction of inks, and advanced surface photochemistry to produce multiplexed glycan microarrays. These arrays feature reduced feature diameters, an increased number of features per array, and precise control of glycan density at each feature.
The versatility of this platform has been validated by printing two distinct glycan microarrays. In the first, different glycans were immobilized to create a multiplexed array. In the second, the density of a single glycan was varied systematically to explore the effect of surface presentation on lectin-glycan binding.
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Microfluidic Incubation Chip for Lectin Binding Studies
For lectin binding studies on these miniaturized microarrays, a microfluidic incubation chip was developed. This chip channels multiple different protein solutions over the array. Using the multiplexed array, binding between eight lectin solutions and five different glycosides was determined, enabling a single array to interrogate the binding between 40 lectin-glycan combinations. The incubation chip was then used on the array with varied glycan density to study the effects of glycan density on lectin binding.
Graduate Student Success at Hunter College
Hunter College welcomes a diverse and accomplished graduate cohort. These scholars have participated in programs such as the National Consortium for Graduate Degrees for Minorities in Engineering and Science (GEM), Louis Stokes Alliance for Minority Participation (LSAMP), McNair Scholars, NIH Initiative to Maximize Student Development (IMSD), NIH Post-Baccalaureate Research Education Program (PrEP), NSF STEM Talent Expansion Program, and the Robert A. Welch Foundation Research Fellowship. The Robert A. Welch Foundation Research Fellowship is a monetary award provided to support a student’s education.
Almost every student in the cohort has served as a peer instructor for chemistry courses, and many have completed an honors thesis, a written work (long essay or multi-chapter document) describing their research. Outside of the classroom, these scholars have pursued techniques relevant to chemistry via industry internships, training as a certified pharmacy technician, and outreach. Outreach refers to activities that engage with the broader community.
In recognition of their academic and research excellence, these new graduate scholars have received generous support from highly competitive Laney Graduate School fellowships. Laney Graduate School is a school that offers advanced degrees.
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