Heat shock proteins and some compounds tested against them.
Malaria remains a threat to human life worldwide with children under the age of 5 being the most vulnerable. Plasmodium falciparum, known as the causative agent of the deadliest malaria, survives both in the mosquito vector and human host. The sudden temperature change seems to not affect the parasite’s cellular system. Heat shock proteins and polyamines are the major house-keepers of the parasite’s cellular system to remain viable, despite the temperature changes that the parasite gets exposed to. While heat shock proteins protect newly synthesized proteins until they are properly folded polyamines are needed for cell differentiation, proliferation, and cell growth. In plants for example, polyamines have been reported to act as molecular chaperones when cells are exposed to unfavorable conditions that could be detrimental to cells. In this review, the role of heat shock proteins and polyamines in plasmodium parasite drug resistance and their role in parasite survival are discussed. The current drugs against malaria as well as the alternative future approach towards malarial drug development are reviewed.
- heat shock proteins
- drug resistance
- Plasmodium falciparum
- drug development
According to the world health organization, malarial cases are expected to double in recent times due to the much global focus to fight the covid-19 pandemic . The global fight against the covid-19 pandemic slows down efforts to control or eliminate malaria as one of the life-threatening diseases worldwide. In 2018, 228 million cases of malaria were reported with 405 000 people died, and in Sub-Saharan Africa, 67% of children under the age of 5 prematurely succumbed to the disease [1, 2]. The currently available drugs in the market are not effective enough and there is a growing concern of reported cases of drug resistance in some parts of the world. These drugs include artemisinin combination therapy which was a promising treatment for malaria. Therefore, there is an urgent need for alternative drugs or vaccines for malaria. Among the six species of malaria causative agents namely,
Heat shock proteins are ubiquitous, highly conserved molecules that occur in all recognized life forms. The constitutively expressed heat shock proteins are generally designated as ‘heat shock cognate’ (Hsc) forms to differentiate them from the inducible heat shock protein (Hsp) forms. The constitutively expressed forms play a housekeeping role, while the inducible forms are normally expressed in response to stress. The role of heat shock proteins is to protect the newly synthesized proteins from misfolding, which could result in the formation of inclusion bodies or truncated proteins that can be toxic to the cellular system of the parasite. On the other hand, a group of proteins known as polyamines is produced in the parasite for proliferation, differentiation, and growth. When merozoite invades red blood cells, polyamines are believed to be at the center of the parasite multiplication process and act as molecular chaperones. For example, when cells that lack polyamines are added with polyamines and exposed to a temperature above 37°C, the cells do survive , signifying that polyamines display chaperone activities. Wide studies conducted in plant biochemistry demonstrated that when plant cells are exposed to abiotic temperature, polyamines protect plant cells and improve growth and production . In P. falciparum, it could be that polyamines do cooperate with heat shock proteins as means for the parasite to survive under harsh conditions. For example, Polyamines protected plasmid DNA strand breaks in vitro and aided the cell survival against irradiation in polyamine deficient
In addition, reports suggest that when polyamines metabolism is disrupted, several cellular processes are affected, including transcription, translation, gene expression regulation, autophagy, and stress resistance. Some studies reported that in fact, polyamines influence the production or synthesis of heat shock proteins, even though it is not clear how this process takes place. Heat shock proteins come in different sizes and activities, whereas polyamines include putrescine, spermidine, and spermine. With
2. The life cycle of
Some of the symptoms of malaria include but not all, fever and headache, these normally display when merozoite invade red blood cells and this stage is essential for the parasite survival. Fever is shown by elevated temperature above 38°C in the human host system. This therefore, puts stress on the cellular system of the parasite thus results in increased production of heat shock proteins for cellular system protection (protein folding). On the other hand, the parasite proliferates when the merozoite invades the red blood cells. The primary role of polyamines includes cell proliferation, differentiation, and growth of which are what the parasite needs at the red blood cell stage in a human host. Therefore, both heat shock proteins and polyamines serve as a shield of the parasite in the human host when exposed to stress conditions [17, 18, 19, 20]. A study reported that the chaperone activities of Hsp70 sequester protein aggregates accumulated in bacteria during antibiotic treatment, therefore reducing the effect of the cure. Also, polyamines such as putrescine and spermidine have been suggested to exhibit chaperone activities when cells are exposed to stressful environments such as antibiotic therapies . Taken together, the role polyamines and heat shock proteins play in a cellular system suggests that
3. Heat shock proteins
The outside milieu affects the in-house activity of the cellular system. If cells are exposed to stressful conditions, several molecular functions could be upset. For cells to remain functional active, the interior system should remain in good condition and if that is not the case, this could lead to cell death. Therefore, heat shock proteins of different sizes perform various functional activities to keep the cellular system in good condition. Molecular chaperone or heat shock proteins perform some activities as housekeepers of the cell, such as foldase, holdase, protein transportation, removal of inclusion bodies, modulation, and stabilization (Table 1). Whereas others are responsible for bringing the substrate for binding to reach a 3-dimensional structure. In
Different kinds of compounds have been synthesized and their effectiveness against heat shock proteins was tested . The complex nature of the
4. The functional activities of Hsp70 in partnership with Hsp40
Both heat shock protein 70 and heat shock protein 40 were first discovered in bacteria that were exposed to stressful conditions, thus these proteins were overexpressed in response to the challenging conditions the bacteria organism was faced with . As a result, the cellular protein structure and functional activities were affected, Hsp70 was able to rescue aggregated and misfolded proteins (Figure 2). The partnership between Hsp70 and Hsp40 plays a major role in helping misfolded proteins to fold and gain their functional activities [31, 32]. To successfully assist misfolded proteins or substrates to fold properly, Hsp70 recognized and bind into the hydrophobic patches. The major role played by Hsp40 is to recognized and present misfolded proteins into an ATP Hsp70 for folding. The ATP is hydrolyzed to ADP, which then allows the substrate to bind to the ADP Hsp70 for folding. Once properly folded, the ADP is then converted to ATP thus releases the properly folded protein. Taken together, newly synthesized protein requires the assistance of heat shock proteins to fold properly, otherwise, they can be toxic to the cells if they are not properly folded.
5. Biosynthesis of polyamines
The synthesis of Polyamines such as putrescine, spermidine, and spermine is driven by
6. Obligate parasites have many “talents” of survival
During their growth in the vertebrate host or mosquito vector,
7. Current drugs are available in the market for malaria
Utmost of the antimalarial drugs aim at the asexual erythrocytic stages of the parasite, therefore named blood schizonticidal drugs. Tissue schizonticidal drugs mark the hypnozoites (dormant stage of the parasite) in the liver, while gametocytocidal drugs destroy sexual erythrocytic formulae of the parasite in the bloodstream and thus inhibit transmission of malaria to mosquito. Sporontocides stop or inhibit the formation of malarial oocysts and sporozoites in an infected mosquito. Chloroquine, quinine, and mefloquine are typically fast-acting schizonticidal drugs. Pyrimethamine, sulphonamides, and sulphone also possess schizonticidal activities, nevertheless, their action is dawdling (Table 2). Primaquine, Tafenoquine, and other novel kinase inhibitors have gametocidal activities. The main sporontocidal drugs are primaquine and praguanil. These antimalarial drugs were considered based on major metabolic differences of the malaria parasite with its host. Nucleic acid metabolism, heme toxification, oxidative stress, and fatty acid biosynthesis are some of the major pathways that were targeted mostly for antimalarial drug design. However, in the chemotherapy of malaria, the emergence of resistance to the available drugs is the major obstacle.
|Structural name||Types of compounds|
|(1) Aryl aminoalcohol compounds|
|(2) Antifolate compounds|
|(3) Artemisinin compounds|
Furthermost of the existing antimalarial drugs have been used for decades and now their use is restricted by the emergence of drug resistance. According to various literature, there are no existing anti-malarial drugs that were developed in a fully rational manner, with a focused attempt to inhibit a known drug target [35, 36, 47]. Instead, in all cases, anti-malarial potency has been identified in animal or
8. Proposed drug candidate
There is an urgent need to develop new chemotherapeutic agents which display schizontocidal activity, thereby overcoming the making of merozoites from erythrocytes. The rise of drug resistance can be overcome by aiming the parasite transmission at the blood stage. Additionally, powerful drug candidates are vital to be explored. These should prove to be potent enough at a single dose to block the parasite transmission at the erythrocytic stage. Both safety and efficacy aspects of novel drug candidates also need distinct consideration to be a matter of great concern for antimalarial drug discovery. The medicinal chemist along with the pharmacologist necessities to work hard for the antimalarial drug development to achieve the desired safety, efficacy, and potency in a single dose molecule [30, 48, 49]. General, to decrease the present malaria load competently, more support is necessary in the long run. If the
9. Conclusion and future perspectives
There has been regular work over the years for the radical treatment of malaria. Improvement of drug confrontation, existence the most problematic obstacle for the achievement of antimalarial therapy, most of the research is oriented towards overcoming the emergence and spread of resistance to existing drugs by one or the other means. Notwithstanding the pressing need, fewer energies have been absorbed in developing new drugs with new mechanism(s) of action. Now for the last periods, pharmaceutical consideration has on receiving more understandings into numerous metabolic or biochemical pathways of the parasite with the expectation to classify and exploit novel drug targets. The study is also underway to establish the mechanism of action of polyamines being influential in the synthesis of heat shock proteins and the role of polyamines being regarded or acting as chaperones in
The author wish to thank the University of Fort Hare for the support to this work. Lastly, wish to thank Dr. RA Mosa for his technical assistance.