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High Affinity Ligands that Target Liver Cell Surface Receptor (CD81) and Inhibit Liver invasion by Plasmodium falciparum Malaria

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Researchers
Hassan Azzazy, Professor of Chemistry
Reem Al Olaby, Qatar Foundation
Rod Balhorn, SHALs Technology, California
Patent Protection

PCT Patent Application Filed
Publications
Identification of a Novel Drug Lead That Inhibits HCV Infection and Cell-to-Cell Transmission by Targeting the HCV E2 Glycoprotein.
PLoS One, . 2014 Oct 30;9(10):e111333. doi:10.1371/journal.pone.0111333. eCollection 2014.

Application

High affinity ligands were discovered that target the liver cell surface receptor (CD81) and prevent subsequent liver invasion by Plasmodium falciparum Malaria. These ligands can be used as a preventative method or  effective treatment for individuals infected with Malaria. Two or three different ligands can be linked to develop selective high affinity ligands (SHALs) which would result in greater inhibition of parasite binding and entry into liver cells.

Problem

Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected anopheles female mosquitoes.In 2013, malaria caused an estimated 584 000 deaths, mostly among African children. Increased malaria prevention and control measures are dramatically reducing the malaria burden in many places, however resistance to antimalarial medicines is a recurring problem. Resistance of P. falciparum to previous generations of medicines, such as chloroquine and sulfadoxine-pyrimethamine (SP), became widespread in the 1970s and 1980s. Oral Artemisinin-based monotherapies are effective in eliminating malaria parasites, and need to be taken as a full seven-day treatment course. However, most patients do not complete the full regimen due to the rapid clinical response – i.e. clearance of signs and symptoms within 2-3 days. This results in incomplete treatment and resistance to artemisinin derivatives. Patients still have persistent parasites in their blood. Without a second drug given as part of a combination, (as is provided with artemisinin-based combination therapies - ACTs), these resistant parasites survive and can be passed on to a mosquito and then another person.  

There are currently no licensed vaccines against malaria or any other human parasite.

Technology

Plasmodium sporozoites are transmitted through the bite of infected mosquitoes and first invade the liver of the mammalian host, as an obligatory step of the life cycle of the malaria parasite. Within hepatocytes, Plasmodium sporozoites reside in a membrane-bound vacuole, where they differentiate into exoerythrocytic forms and merozoites that subsequently infect erythrocytes and cause the malaria disease. Plasmodium sporozoite targeting to the liver is mediated by the specific binding of major sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related anonymous protein, to glycosaminoglycans on the hepatocyte surface, notably the tetraspanin CD81 receptor, a putative receptor for hepatitis C virus.Generating high affinity ligands against malarial sporozoites provides a solution to this public health burden. These compounds bind to cell surface receptor CD81 and either; physically block sporozoites binding to cells displaying CD81 (liver & blood cells), or modify the structure of the binding site, thus preventing attachment and subsequent entry into the host cells.

Using “AutoDock”, an automated docking tool, a set of 36 ligands were discovered where 72% (26 out of 36) were revealed to bind to CD81 through binding assays. Linking together two or three of these ligands generated small molecules called selective high affinity ligands (SHALs) that exhibit very high affinities to their targets.

These compounds and their analogs block sporozoites from entering the cell and possibly reduce the potential inflammation and other pathologies associated with Malarial infections.

Advantages

●  Highly specific ligands prevent malaria entry and cell to cell transmission in a genotype-independent manner, making them more effective than standard treatments with less side effects.

●  Four of the ligand analogues are already FDA approved compounds (used for treatment of depression and other neurological disorders).

●  Additional new compounds have also been discovered which block entry of different species of malaria parasites into cultured liver cells.