UP researcher’s team discovers new compounds with the potential to eliminate malaria

The University of Pretoria (UP) has discovered new potent chemical compounds that show potential as candidates for both the treatment and elimination of malaria.

Professor Lyn-Marie Birkholtz, Professor in Biochemistry and South African Research Chair in Sustainable Malaria Control (part of the South African Research Chair Initiative, SARChI), was part of an international team that published this discovery in the journal Nature Communications on 11 January. “The breakthrough involves the identification of unique compounds that are able to kill several stages of the malaria-causing parasite and can block the transmission of the parasite between humans and mosquitoes,” she explained.

The deadly human malaria parasite Plasmodium falciparum occurs in South Africa. These parasites are transmitted to humans by female Anopheles mosquitoes. The only means of killing the parasite itself is to use chemical drugs, but new antimalarial drugs are urgently needed to address the growing concern of antimalarial drug resistance.

Prof Birkholtz describes the parasite as a “shape shifter” since it can take on multiple forms while in humans. Some of the forms cause disease and others allow the parasite to be transmitted back to mosquitoes to continue the life cycle. Prof Birkholtz states: “To eliminate malaria, it is essential that we have the necessary tools to kill all these different forms of the parasite. We can then cure patients of the disease but, importantly, also block the malaria transmission cycle. This is the only way to achieve malaria elimination.

South Africa is leading regional malaria elimination efforts as part of four frontline countries in southern Africa including Namibia, Botswana and Eswatini.

In an innovative strategy, the team looked for new chemical compounds that can do exactly this, but that are completely new so that the parasite does not have resistance against them. The team runs a unique research platform on the African continent, in which all of these stages of the malaria parasite can be produced in the lab and be used to test chemical compounds. The team discovered compounds that kill the disease-causing form and compounds that blocked the parasite from infecting mosquitoes in the lab.

Two potent compounds target processes essential to the parasite’s survival: one is a clinical candidate against tuberculosis and blocks cell membrane synthesis and another is an anti-cancer candidate that targets epigenetic mechanisms (mechanisms that control cell fate beyond the genome). “This is the first time that these compounds were shown to have activity against malaria parasites and since they are not toxic to humans, they show the potential to be developed as antimalarials for both the treatment and elimination of the disease,” said Prof Birkholtz.

The discovery was made possible by the team’s use of an open-source chemical compound set called the Pandemic Response Box, developed by the Switzerland-based Medicines for Malaria Venture (MMV) and the Drugs for Neglected Diseases Initiative (DNDi). This compound box contains compounds that can be used for drug repurposing/repositioning, a process where drugs that have activity against a specific disease (e.g. cancer) can be reused for another disease (e.g. malaria). Dr James Duffy, MMV Project Director, describes the discovery “as an important breakthrough that emphasises the potential to use existing drugs as inspiration for drug discovery projects targeting different diseases. Never before has this been more important than in light of current outbreaks, where the rapid response to discover new chemicals able to kill infectious organisms is essential.”

Prof Birkholtz directs the parasite cluster of the UP Institute for Sustainable Malaria Control (ISMC), a multidisciplinary institute with a focus on integrated innovations towards malaria elimination in South Africa. Professor Tiaan de Jager, Director of the ISMC and Dean of Health Sciences at UP, said: “A discovery of this kind attests to the leading expertise in antimalarial drug discovery at UP, and in South Africa, addressing African-centred societal challenges. This work also shows the commitment of scientists at UP to contribute to the United Nation’s Sustainable Development Goal for Good Health and Wellbeing.”

Prof Birkholtz’s team led the transmission-blocking drug discovery effort as partner in the South African Malaria Drug Discovery Consortium (SAMDD) that includes two other South African Research Chairs, Professor Kelly Chibale (Chair in Drug Discovery at the Drug Discovery and Development Centre, H3D, at the University of Cape Town) and Professor Lizette Koekemoer (Chair in Medical Entomology at the WITS Institute for Research on Malaria at the University of the Witwatersrand) as well as scientists from the Council for Scientific and Industrial Research and international partners from the USA and Spain. The work has benefitted from sustained funding from the MMV and the Medical Research Council’s Strategic Health Innovation Programme (SHIP) and affirms that investments in health innovations places South Africa at the forefront of discovery.

Story by: The University of Pretoria 

What’s Ahead for SARS-CoV-2 Research in 2021

Ever since the virus now known as SARS-CoV-2 was first identified and sequenced by researchers in China a year ago, a tidal wave of research on the pathogen and its associated disease, COVID-19, has swamped the scientific literature. Indeed, an analysis posted as a preprint last month found that more than 84,000 papers related to COVID-19 were published in the first 11 months of 2020.

Even given that output and the recent rollout of vaccines against the disease, researchers who study the virus aren’t ready to put it on ice and move on to other problems. Here are some of the key areas where we’re likely to see advances in understanding this year.

Where did it come from?

Teasing out SARS-CoV-2’s origin is important, says disease ecologist Jonathan Epstein of EcoHealth Alliance, because knowing how the virus got into humans could yield clues about how to avoid future spillovers. The SARS outbreaks of 2003 and 2004 spurred research (of which Epstein was a part) that identified horseshoe bats as a reservoir for this family of coronaviruses, he notes, but it’s still not known exactly how either virus made it from bats to people. Understanding whether SARS-CoV-2 jumped directly from bats into people, or whether it first infected a wild or domesticated intermediary species, would help in pinpointing particular human activities that could be putting us at risk of future zoonotic events, he says.

The World Health Organization (WHO) has convenened a team to investigate the virus’s origins that began traveling to China early this month, WHO head Tedros Adhanom Ghebreyesus said in a January 5 briefing. According to WHO spokesperson Tarik Jašarević, the team’s plans include reviewing hospital records from late 2019 to identify illnesses that might have been COVID-19, interviewing people who were the first known cases, and finding out what animals were traded at a market in Wuhan associated with some early infections, and possibly other local markets around the time of the outbreak, and where those animals came from. Jašarević did not say when the team’s findings might be made available.

In addition to prevention, another benefit of knowing the animal origins of coronaviruses is the opportunity to design medicines against them in advance, namely, “broadly neutralizing antibodies that can hit not just SARS-2, but other related coronaviruses that we know are in animal reservoirs,” says virologist Kartik Chandran of Albert Einstein College of Medicine in New York. That’s a long-term goal of his current work on identifying effective antibodies that can be used as a COVID-19 drug. And, he says, it will also be important to figure out how to develop vaccines that confer protection against a broad swath of such coronaviruses. “From a research standpoint, in the next few years, that’s going to be a major challenge.”

More treatment options

Even with effective vaccines, humanity is likely stuck with SARS-CoV-2, much like the cold-causing coronaviruses and influenza, Chandran says. That means there’s an ongoing need for effective treatments for the disease. One issue with current monoclonal antibody treatments, he notes, is that they require large volumes to be administered by IV, creating logistical challenges. “If we can get these things to be potent enough, we ideally would be able to give them by intramuscular injection, rather than giving them IV—that would make a huge difference,” he says. “But that’s going to require a jump in potency that’s quite significant.”

So far, one standalone monoclonal antibody, bamlanivimab, and a combination of two, casirivimab and imdevimab, have received emergency use authorization from the US Food and Drug Administration (FDA). Both treatments were tested in clinical trials on people with mild or moderate disease, and the studies found that those who received them had about one-third the risk of visiting the ER or being hospitalized in the following four weeks compared with patients who got a placebo. Other currently available treatments include the antiviral remdesivir and the steroid dexamethasone, each of which are used for some hospitalized patients, and convalescent plasma, which, according to a small trial published this week, halved the risk of severe respiratory illness when given within three days of the onset of symptoms.

“We were encouraged to see the quick pace of development of the monoclonal antibodies,” says Esther Krofah, the executive director of the FasterCures center at the nonprofit Milken Institute. “But I think there’s still a lot more to be done, particularly in an outpatient setting.” In particular, a small-molecule drug that could be taken by patients at home to reduce their chances of hospitalization would alleviate some of the pressure on the healthcare system. One such drug she’s keeping an eye on, camostat mesilate, is a protease inhibitor currently being tested in multiple clinical trials.

FasterCures is tracking more than 300 prospective vaccines and treatments for COVID-19 that are in various stages of development. Krofah says she expects many current clinical trials not to yield conclusive results due to poor design or problems recruiting enough patients. One promising tack, she says, are the so-called master protocol studies that compare different treatments both with each other and with a placebo.

A series of such trials sponsored by the National Institutes of Health, for example, several of which are expected to be completed later this year, are testing immune modulators, monoclonal antibodies, and blood thinners in groups of COVID-19 patients. In other trials, some repurposed antibiotics and an antifungal have also shown promise and could make it to the clinic this year, says Yasmeen Long, also of FasterCures.

Variant surveillance

As SARS-CoV-2 continues to mutate, researchers will need to determine whether available vaccines are effective against newer variants, Chandran says, such as the B.1.1.7 and 501.V2 variants that have drawn much attention in recent weeks. Akiko Iwasaki, an immunologist at Yale University, says that while current variants are “likely going to be covered by the existing vaccines, in the future, there may be new variants that can emerge that would evade the current vaccine”—meaning surveillance of viral variants should be a priority.

To date, the US has sequenced 58,560 SARS-CoV-2 samples, compared to the UK’s 209,038, The New York Times reports, but a Centers for Disease Control and Prevention official tells CNN that the agency and its partners are working to double the number of viral sequences they post publicly each week to about 6,500.

The long haul

One of Iwasaki’s current projects is profiling the immune responses of people whose COVID-19 symptoms have lasted for months, a phenomenon known as long COVID. “Right now, there are thousands of people suffering from long COVID,” she says. “But there’s very little insight as to how the disease is caused and prolonged for so many people.”

Understanding the mechanism of the disease could point the way to ways of treating it, she says, and might also shed light on other cases of chronic disease associated with an initial viral infection. In particular, after recently finding that hospitalized COVID-19 patients harbor distinct antibodies against their own proteins, known as autoantibodies, she and her colleagues have begun investigating whether such autoantibodies are at play in long COVID.

 

Story by Shawna Williams, for The Scientist