91制片厂

Three-dimentional structure of antimalarial drug target PfATP4 with its associated protein PfABP.

Scientists from 91制片厂鈥檚 College of Medicine and Columbia University鈥檚 Irving Medical Center have uncovered a crucial structural feature of a key malaria drug target, known as PfATP4, and discovered a previously unknown binding partner that could reshape antimalarial drug design.

The team revealed a three-dimensional structure of a malaria parasite鈥檚 sodium pump, known as P. falciparum P-type ATPase, or PfATP4. Found on the plasma membrane of a malaria-causing parasite, the pump pushes sodium out of a parasite鈥檚 cytoplasm to help the parasite survive. The findings were published today in Nature Communications.

Malaria, often caused by a species of parasite known as Plasmodium falciparum, continues to , as rising drug resistance undermines decades of progress against the mosquito-borne infectious disease. Several clinical candidates, including the experimental drug Cipargamin, directly inhibit PfATP4 鈥� but mutations causing resistance to the drug have readily emerged.

Using cryogenic electron microscopy, which projects an electron beam through a frozen sample, the researchers visualized PfATP4 purified directly from parasites grown in human red blood cells. This high-resolution structure revealed the precise organization of PfATP4鈥檚 ATP- and sodium-binding sites, allowing scientists to map where resistance mutations occur.

During the study, the team identified an entirely new protein, which they named PfATP4 Binding Protein (PfABP). PfABP tightly associates with PfATP4, is essential for parasite survival and appears to stabilize and regulate PfATP4鈥檚 function. The researchers鈥� experiments showed that loss of PfABP led to the rapid degradation of PfATP4 and death of the parasite.

"The discovery of ABP was possible because we isolated the pump directly from malaria parasites,鈥� said co-lead author Anurag Shukla, PhD, a research instructor at Drexel. 鈥淭his required hundreds of liters of growth medium with the parasites growing in human red blood cells.鈥�

Looking at structural comparisons with related enzymes called P-type ATPases, the authors suggest that PfABP functions much like regulatory subunits in human ion pumps 鈥� pointing to a new class of drugs against pathogens. Because PfABP is largely unchanged across malaria parasites but absent from humans, it offers a unique therapeutic opportunity with potentially less risk of long-term harmful side effects, the authors suggested.

鈥淭his discovery changes the way we think about PfATP4 as a drug target,鈥� said Akhil Vaidya, co-senior author and professor at Drexel鈥檚 College of Medicine and also a co-inventor of an anti-malaria agent. 鈥淧fABP not only stabilizes the pump but likely modulates its activity. Targeting this interaction may provide a more durable therapeutic strategy against malaria.鈥�

The findings may provide a blueprint for next-generation drug discovery, the authors argued, offering ways to design molecules that target not only PfATP4, but also its essential partner PfABP.

鈥淓very year, malaria parasites adapt to outsmart our medicines,鈥� said Chi-Min Ho, PhD, co-senior author and assistant professor at Columbia. 鈥淏y revealing this hidden partnership within the parasite鈥檚 sodium pump, we have uncovered a vulnerability that can be exploited for new therapies.鈥�

The paper 鈥淓ndogenous structure of antimalarial target PfATP4 reveals an apicomplexan-specific P-1 type ATPase modulator鈥� is available online .

In addition to Vaidya, Shukla and Ho, additional authors include co-lead author Meseret Haile, a doctoral student at Columbia; Michael W. Mather, PhD; Suyash Bhatnagar, PhD and Joanne M. Morrisey, from Drexel and James Zhen, PhD, and Zhening Zhang, PhD, from Columbia.This research was supported by funding from the National Institutes of Health (DP5OD029613, R01AI132508 and R01AI154499).