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

Abstract

: Parasite Plasmodium falciparum is continuously successful to give a challenge to human beings by changing itself against most of the antimalaria drugs and its consequences can be seen by huge death each year due to malaria especially in the poor and developing country. Due to its ability to drug resistance, 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-L-homocysteine hydrolase regulates methyltransferase reactions. In this way, SAH hydrolase inhibitors could 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.

Antiparasitic activity of FLLL-32 against four Babesia species, B. bovis, B. bigemina, B. divergens and B. caballi, and one Theileria species, Theileria equi in vitro, and Babesia microti in mice

“…Several nucleoside inhibitors of SAHH have therefore been synthesized, having pharmacological and biological effects such as antiviral effects (Chiang, 1998;Clerq, 1998). S-adenosylhomocysteine hydrolase was shown to be an interesting target for the development of novel anti-malarial agents (Bitonti et al, 1990;Kitade et al, 2003;Nakanishi et al, 2005;Chandra et al, 2021). SAHH gene from Plasmodium falciparum (PfSAHH) was well characterized (Creedon et al, 1994;Bujnicki et al, 2003;Tanaka et al, 2004) however, no studies have been conducted on B. bovis.…”

Current Strategies on the Enantioselective Synthesis of Modified Nucleosides

“…It would be no exaggeration to say that nucleoside analogues are the most significant contributors to alleviating different diseases [1][2][3][4] that have been faced by human society. These analogues have saved millions of lives since the first approval of ARA-A (adenine arabinoside) by the FDA in 1976 for the treatment of different viruses.…”

“…It would be no exaggeration to say that nucleoside analogues are the most significant contributors to alleviating many of the different diseases faced by human society. [1][2][3][4] These analogues have saved millions of lives since the approval of ARA-A (adenine arabinoside) by the FDA in 1976 for the treatment of different viruses. Since then, belief and faith have increased and continued until today, which can be reflected by the fact that 30% of marketed drugs belong to the nucleoside family (Figure 1).…”