S-adenosyl-L-homocysteine Hydrolase: Its Inhibitory Activity Against Plasmodium falciparum and Development of Malaria Drugs

Girish       Chandra; Samridhi       Patel; Manoj       Panchal; Durg    Vijay    Singh

Abstract

Parasite Plasmodium falciparum is continuously giving a challenge to human beings by changing itself against most of the antimalarial drugs and its consequences can be seen in the form of a huge number of deaths each year especially in the poor and developing country. Due to its drug resistance ability, new drugs are regularly needed to kill the organism. Many new drugs have been developed based on different mechanisms. One of the potential mechanisms is to hamper protein synthesis by blocking the gene expression.

S-Adenosyl-L-homocysteine (SAH) hydrolase is a NAD+ dependent tetrameric enzyme, which is responsible for the reversible hydrolysis of AdoHcy to adenosine and L-homocysteine, has been recognized as a new target for antimalarial agents since the parasite has a specific SAH hydrolase. The inhibition of SAH hydrolase causes the intracellular accumulation of S-Adenosyl-L-homocysteine, elevating the ratio of SAH to S-adenosylmethionine (SAM) and inhibiting SAM-dependent methyltransferase that catalyzes methylation of the capped structure at the 5′-terminus of mRNA, and other methylation reaction which is essential for parasite proliferation. In other words, S-Adenosyl-Lhomocysteine hydrolase regulates methyltransferase reactions. In this way, SAH hydrolase inhibitors can be used for the treatment of different diseases like malaria, cancer, viral infection, etc. by ultimately stopping the synthesis of protein. Many antiviral drugs have been synthesized and marketed which are based on the inhibition of SAH hydrolase.

This review summarises the development of SAH inhibitors developed over the last 20 years and their potentiality for the treatment of malaria.

Keywords: S-Adenosyl-L-homocysteine hydrolase, antimalarial compound, modified nucleoside, enzyme inhibitor, neplanocin, drug design.

Graphical Abstract

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Mini-Reviews in Medicinal Chemistry

S-adenosyl-L-homocysteine Hydrolase: Its Inhibitory Activity Against Plasmodium falciparum and Development of Malaria Drugs

Abstract

Graphical Abstract