Proline, a unique amino acid whose polymer, polyproline II helix, and its analogues are involved in many biological processes: a review.

Proline is a unique amino acid in that its side-chain is cyclised to the backbone, thus giving proline an exceptional rigidity and a considerably restricted conformational space. Polyproline forms two well-characterized helical structures: a left-handed polyproline helix (PPII) and a right-handed polyproline helix (PPI). Usually, sequences made only of prolyl residues are in PPII conformation, but even sequences not rich in proline but which are rich in glycine, lysine, glutamate, or aspartate have also a tendency to form PPII helices. Currently, the only way to study unambiguously PPII structure in solution is to use spectroscopies based on optical activity such as circular dichroism, vibrational circular dichroism and Raman optical activity. The importance of the PPII structure is emphasized by its ubiquitous presence in different organisms from yeast to human beings where proline-rich motifs and their binding domains are believed to be involved in vital biological processes. Some of the domains that are bound by proline-rich motifs include SH3 domains, WW domains, GYF domains and UEV domains, etc. The PPII structure has been demonstrated to be essential to biological activities such as signal transduction, transcription, cell motility, and immune response.

Current status of the small molecule anti-HIV drugs in the pipeline or recently approved.

Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS) with high morbidity and mortality rates. Treatment of AIDS/HIV is being complicated by increasing resistance to currently used antiretroviral (ARV) drugs, mainly in low- and middle-income countries (LMICs) due to drug misuse, poor drug supply and poor treatment monitoring. However, progress has been made in the development of new ARV drugs, targeting different HIV components (Fig. 1). This review aims at presenting and discussing the progress made towards the discovery of new ARVs that are at different stages of clinical trials as of July 2024. For each compound, the mechanism of action, target biomolecule, genes associated with resistance, efficacy and safety, class, and phase of clinical trial are discussed. These compounds include analogues of nucleoside reverse transcriptase inhibitors (NRTIs) - islatravir and censavudine; non-nucleoside reverse transcriptase inhibitors (NNRTIs) - Rilpivirine, elsulfavirine and doravirine; integrase inhibitors namely cabotegravir and dolutegravir and chemokine coreceptors 5 and 2 (CC5/CCR2) antagonists for example cenicriviroc. Also, fostemsavir is being developed as an attachment inhibitor while lenacapavir, VH4004280 and VH4011499 are capsid inhibitors. Others are maturation inhibitors such as GSK-254, GSK3532795, GSK3739937, GSK2838232, and other compounds labelled as miscellaneous (do not belong to the classical groups of anti-HIV drugs or to the newer classes) such as obefazimod and BIT225. There is a considerable progress in the development of new anti-HIV drugs and the effort will continue since HIV infections has no cure or vaccine till now. Efforts are needed to reduce the toxicity of available drugs or discover new drugs with new classes which can delay the development of resistance.

Recent developments in antimalarial drug discovery.

Although malaria remains a big burden to many countries that it threatens their socio-economic stability, particularly in the countries where malaria is endemic, there have been great efforts to eradicate this disease with both successes and failures. For example, there has been a great improvement in malaria prevention and treatment methods with a net reduction in infection and mortality rates. However, the disease remains a global threat in terms of the number of people affected because it is one of the infectious diseases that has the highest prevalence rate, especially in Africa where the deadly Plasmodium falciparum is still widely spread. Methods to fight malaria are being diversified, including the use of mosquito nets, the target candidate profiles (TCPs) and target product profiles (TPPs) of medicine for malarial venture (MMV) strategy, the search for newer and potent drugs that could reverse chloroquine resistance, and the use of adjuvants such as rosiglitazone and sevuparin. Although these adjuvants have no antiplasmodial activity, they can help to alleviate the effects which result from plasmodium invasion such as cytoadherence. The list of new antimalarial drugs under development is long, including the out of ordinary new drugs MMV048, CDRI-97/78 and INE963 from South Africa, India and Novartis, respectively.

A review of recent advances in anti-tubercular drug development.

Tuberculosis is a global threat but in particular affects people from developing countries. It is thought that nearly a third of the population of the world live with its causative bacteria in a dormant form. Although tuberculosis is a curable disease, the chances of cure become slim as the disease becomes multidrug-resistant and the situation gets even worse as the disease becomes extensively drug-resistant. After approximately 5 decades without any new TB drug in the pipeline, there has been some good news in the recent years with the discovery of new drugs such as bedaquiline and delamanid as well as the discovery of new classes of anti-tubercular drugs. Some old drugs such as clofazimine, linezolid and many others which were not previously indicated for tuberculosis have been also repurposed for tuberculosis and they are performing well.