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HIV/AIDS
Published in Patricia G. Melloy, Viruses and Society, 2023
Nucleoside/nucleotide analogs are drugs that are competitive inhibitors of the reverse transcriptase that is needed to copy the HIV genome. One of the most famous drugs in this category is AZT (Ojikutu 2008b; Lostroh 2019). AZT can be used to reduce the chance of mother-to-child transmission of HIV, which can occur in utero, during birth, or just after birth (Ojikutu 2008b). Other categories of drugs include non-nucleoside inhibitors of reverse transcriptase, drugs that block fusion of the virus with the cell, and drugs that block the integration of the genome into the host’s cellular genome, among others. One can look at every stage of the HIV life cycle as a possible point of attack for an antiretroviral drug (Lostroh 2019; Gulick and Flexner 2019). Another important class of anti-HIV drugs are the protease inhibitors that block the viral enzyme called a protease that is needed for the maturing of the virus. Protease inhibitors were developed through “rational drug design,” meaning that the crystal structure of the protease was resolved, and then a drug was designed to block it, rather than testing an existing compound for its effectiveness against the virus (Lostroh 2019).
The Viruses
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Despite the difficulty of the problem some effective antiviral drugs have been developed against herpesviruses and retroviruses. The nucleoside analogue acycloguanosine (Acyclovir) is activated by phosphorylation via thymidine kinase, a herpesvirus encoded enzyme. The phosphorylated analogue acts then to inhibit the activity of the virus-encoded polymerase. Nucleoside and nonnucleoside inhibitors have been developed against retroviral infections as a result of the massive efforts developed in response to the AIDS epidemic (see below). Nucleoside analogues such as azidothymidine (AZT) selectively inhibit reverse transcriptase (RT) and thereby inhibit the replication of the retroviruses including HIV. A variety of nucleoside analogs have been produced to combat HIV infections (e.g., ddl, didanosine). The need for additional antiviral drugs against HIV has been driven, in part, by the ability of retroviruses like HIV to mutate and become resistant to the effects of drugs that have been developed. The introduction of protease inhibitors like nelfinavir has provided additional types of drugs active against HIV infection. These drugs in combination with RT inhibitors have provided new hope in the battle against AIDS. However, before long-term success against HIV is achieved elimination of sites of latent virus production and continued development of drugs against resistant strains will be required.
Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
At the time of writing, ongoing clinical trials have identified promising inhibitors of the viral replication machinery and host cell entry mechanisms. Other avenues to combating SARS-CoV-2 include blockers and/or inhibitors of alternate cell entry pathways and in particular, proteases expressed by the host and/or virus, which are critical for viral entry and/or pathogenesis. All drug targets discussed here, and agents that may act on them, are summarized in Table 10.1. In some cases, druggable protease inhibitors already exist, and in other cases are under intense study and development. Given the worldwide effort devoted to solving this global problem, safe and effective antivirals are on the near horizon.
Evaluation of the toxicological effects of favipiravir (T-705) on liver and kidney in rats: biochemical and histopathological approach
Published in Drug and Chemical Toxicology, 2023
Adem Kara, Seda Yakut, Cuneyt Caglayan, Tuğçe Atçalı, Aykut Ulucan, Fatih Mehmet Kandemir
Favipiravir is an RNA polymerase (RNAP) inhibitor which is a family of enzymes and responsible for transcribing the information in a DNA or RNA molecule as an RNA molecule. The process of copying the information contained in a gene as an RNA molecule is called transcription. RNAP enzymes found in many viruses and living things allow genes to be read as RNA strands in the cells. Molecular studies revealed that viral proteases play a critical role in the life cycle of many viruses, either by influencing the cleavage of high molecular weight viral polyprotein precursors for the functional products or by catalyzing the processing of structural proteins. Nowadays, many types of research are conducted on protease inhibitors to treat infections caused by many RNA and DNA viruses, such as HIV, HCV, Picornaviruses, RSV, Herpes viruses, Rotavirus, and SARS (Mendenhall et al. 2011b, Goldhill et al. 2018, Musa 2020).
Menthol augmented niosomes for enhanced intestinal absorption of lopinavir
Published in Pharmaceutical Development and Technology, 2022
Noha D. Fayed, Ebtesam A. Essa, Gamal M. El Maghraby
Lopinavir is dicarboxylic acid diamide antiretroviral protease inhibitor (Figure 1). It is a specific reversible protease inhibitor that is employed for protection and cures against immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome. It was the first HIV protease inhibitor approved for use (Flexner et al. 2010; Patel 2012). However, lopinavir exhibit poor oral bioavailability due to its low aqueous solubility and extensive pre-systemic disposition by cytochrome P450, in addition to P-glycoprotein intestinal efflux, which can minimize intestinal uptake (Patel et al. 2014; Garg et al. 2016; Fayed et al. 2022). The available formulation is a combined chemotherapy of lopinavir with ritonavir. Ritonavir is incorporated as a potent cytochrome P450 inhibitor, therefore, augments the oral bioavailability of lopinavir. However, ritonavir has some gastrointestinal side-effects, and the pharmacological action of the fixed dose combination is mainly due to lopinavir. Lopinavir has turned out to be the main component in the combined therapy; hence, there is a need for a formulation free from ritonavir (Patel et al. 2017). Accordingly, development of alternative approaches to improve the oral bioavailability of lopinavir is important to avoid coadministration of the less potent toxic ritonavir.
Signal peptide peptidase: a potential therapeutic target for parasitic and viral infections
Published in Expert Opinion on Therapeutic Targets, 2022
Christopher Schwake, Michael Hyon, Athar H. Chishti
For example, Chagas’ disease suffers from noncompliance of standard drugs due to the side effects and diminished effectiveness against chronic infection. HIV protease inhibitors are taken for patients’ entire lifetime owing to their tolerability and effectiveness. The usage of HIV protease inhibitors as another treatment option for parasitic diseases should be considered given the limitations of noncompliance and cost in preventing millions of people from achieving effective therapy. Although long-term usage of HIV protease inhibitors is tolerated by HIV patients, attention should be paid for the inhibition of cytochrome P450 by several such inhibitors [92,93]. Development of parasite-specific SPP inhibitors is a wide-open avenue of future research, which is unlikely to be hindered by technological or methodical limitations. Nonetheless, the major technical challenge for the development of novel SPP inhibitors remains with the differential specificity of these compounds against the pathogen versus host target proteases.