New Perspectives for the Treatment of HIV Infections

1998 ◽  
Vol 63 (4) ◽  
pp. 449-479 ◽  
Author(s):  
Erik De Clercq
Keyword(s):  
Reverse Transcriptase ◽  
Binding Site ◽  
Substrate Binding ◽  
Hiv Infections ◽  
Reverse Transcriptase Inhibitors ◽  
Substrate Binding Site ◽  
Hiv Inhibition ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Replicative Cycle

The HIV replicative cycle reveals several virus-specific events that could function as targets for chemotherapeutic intervention. The compounds that are presently available as anti-HIV drugs are targeted at either the substrate binding site of the reverse transcriptase (zidovudine, didanosine, zalcitabine, stavudine, lamivudine) or a non-substrate binding site of the reverse transcriptase (nevirapine, delavirdine), or the viral protease (saquinavir, ritonavir, indinavir, nelfinavir). Remarkable clinical efficacy has been observed with combinations of different reverse transcriptase inhibitors and protease inhibitors. It may be anticipated that with the advent of newer and more efficient compounds the effectiveness of HIV inhibition could still be improved upon and the prospects for a definitive cure of the disease may be accomplished. An account with 107 references.

scholarly journals Anti-HIV Drug Discovery, Development and Synthesis of Delavirdine: Review Article

2019 ◽  
pp. 1-16 ◽  
Author(s):  
Wollela Behja ◽  
Mudin Jemal
Keyword(s):  
Life Cycle ◽  
Reverse Transcriptase ◽  
Genetic Material ◽  
Amino Acid Sequences ◽  
Surface Binding ◽  
Reverse Transcriptase Inhibitors ◽  
Fusion Inhibitors ◽  
Critical Components ◽  
Hiv Drugs ◽  
Anti Hiv

Viruses are the smallest infectious agents of animal and plant tissues. Viruses are totally dependent on living cells to survive as they utilize the host cell's own replication processes, in order to reproduce themselves. HIV is the causative agent of AIDS. HIV is an unusually difficult to treat because it incorporate its own genetic material into the genome of an infected host cell. It infects T cells that carry the CD4 antigen on their surface. Binding and fusion, reverse transcription, integration, transcription, assembly and budding are the major steps of the HIV life cycle. The HIV/AIDS disease is treated by interrupting the HIV life cycle with specially designed drugs. The discovery of effective drugs against HIV has focused on targeting various critical components of the replication cycle of HIV. Depending on the target within the HIV replicative cycle they interact with, anti-HIV compounds are categorized into six groups. These are: nucleoside (nucleotide) reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The development of effective anti-HIV drugs is difficult due to wide variations in nucleotide and amino acid sequences. The development of anti-HIV drug passes through several important steps. This includes development from α-APA to ITU, ITU to DATA, DAPY to etravirine. Fosdevirine, lersivirine and rilpivirine are among the drugs that were undergoing clinical development and finally only rilpivirine was approved by FDA. The synthesis of delavirdine employs the use of heterocyclic rings like substituted pyridine and indole.

scholarly journals New developments in anti-HIV chemotherapy

2001 ◽  
Vol 73 (1) ◽  
pp. 55-66 ◽  
Author(s):  
Erik De Clercq
Keyword(s):  
Reverse Transcriptase ◽  
Viral Entry ◽  
Hiv Infections ◽  
Viral Envelope ◽  
Reverse Transcriptase Inhibitors ◽  
Intact Cells ◽  
Metabolic Characteristics ◽  
Glycoprotein Gp120 ◽  
Anti Hiv Agents ◽  
Anti Hiv

Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, tenofovir (PMPA), and disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, and emivirine; and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir. In addition, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120; (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5; (iii) virus-cell fusion; (iv) viral assembly and disassembly; (v) proviral DNA integration; and (vi) viral mRNA transcription. Also, new NRTIs, NNRTIs, and PIs have been developed that possess respectively improved metabolic characteristics, or increased activity against NNRTI-resistant HIV strains or, as in the case of PIs, a different, nonpeptidic scaffold. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells.

scholarly journals A Review of Electroanalytical Techniques for Determination of Anti-HIV Drugs

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Burçin Bozal ◽  
Bengi Uslu ◽  
Sibel A. Özkan
Keyword(s):  
Reverse Transcriptase ◽  
Immune Deficiency Syndrome ◽  
Deficiency Syndrome ◽  
Reverse Transcriptase Inhibitors ◽  
Pharmaceutical Dosage Forms ◽  
Fusion Inhibitors ◽  
Voltammetric Techniques ◽  
Hiv Drugs ◽  
Anti Hiv

Until now after the human immunodeficiency virus (HIV) was discovered as the then tentative aetiological agent of acquired immune deficiency syndrome (AIDS), exactly 25 anti-HIV compounds have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, lamivudine, abacavir, stavudine, and emtricitabine), nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir), nonnucleoside reverse transcriptase inhibitors (NNRTIs: efavirenz, nevirapine, delavirdine, and etravirine), protease inhibitors (PIs: ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, lopinavir, fosamprenavir, atazanavir, tipranavir and darunavir), fusion inhibitors (FIs: enfuvirtide), coreceptor inhibitors (CRIs: maraviroc), and integrase inhibitors (INIs: raltegravir). The present paper submitted the use of various electroanalytical techniques for the determination of anti-HIV drugs. This paper covers the time period from 1990 to 2010 including voltammetric techniques that were reported. Presented application concerns analysis of anti-HIV drugs from pharmaceutical dosage forms and biological samples.

scholarly journals Twenty-six years of HIV science: an overview of anti-HIV drugs metabolism

2011 ◽  
Vol 47 (2) ◽  
pp. 209-230 ◽  
Author(s):  
Carolina Horta Andrade ◽  
Lenis Medeiros de Freitas ◽  
Valéria de Oliveira
Keyword(s):  
Reverse Transcriptase ◽  
Pharmacokinetic Profile ◽  
Antiretroviral Drugs ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Entry Inhibitors ◽  
Fusion Inhibitors ◽  
Hiv Research ◽  
Hiv Drugs ◽  
Anti Hiv

From the identification of HIV as the agent causing AIDS, to the development of effective antiretroviral drugs, the scientific achievements in HIV research over the past twenty-six years have been formidable. Currently, there are twenty-five anti-HIV compounds which have been formally approved for clinical use in the treatment of AIDS. These compounds fall into six categories: nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), cell entry inhibitors or fusion inhibitors (FIs), co-receptor inhibitors (CRIs), and integrase inhibitors (INIs). Metabolism by the host organism is one of the most important determinants of the pharmacokinetic profile of a drug. Formation of active or toxic metabolites will also have an impact on the pharmacological and toxicological outcomes. Therefore, it is widely recognized that metabolism studies of a new chemical entity need to be addressed early in the drug discovery process. This paper describes an overview of the metabolism of currently available anti-HIV drugs.

Comprehensive in silico Study of GLUT10: Prediction of Possible Substrate Binding Sites and Interacting Molecules

2020 ◽  
Vol 21 (2) ◽  
pp. 117-130 ◽  
Author(s):  
Mohammad J. Hosen ◽  
Mahmudul Hasan ◽  
Sourav Chakraborty ◽  
Ruhshan A. Abir ◽  
Abdullah Zubaer ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Binding Site ◽  
Glucose Transporter ◽  
Substrate Binding ◽  
Mutation Screening ◽  
Homology Model ◽  
Connective Tissue Disorder ◽  
Crystallographic Structure ◽  
Substrate Binding Site

Objectives: The Arterial Tortuosity Syndrome (ATS) is an autosomal recessive connective tissue disorder, mainly characterized by tortuosity and stenosis of the arteries with a propensity towards aneurysm formation and dissection. It is caused by mutations in the SLC2A10 gene that encodes the facilitative glucose transporter GLUT10. The molecules transported by and interacting with GLUT10 have still not been unambiguously identified. Hence, the study attempts to identify both the substrate binding site of GLUT10 and the molecules interacting with this site. Methods: As High-resolution X-ray crystallographic structure of GLUT10 was not available, 3D homology model of GLUT10 in open conformation was constructed. Further, molecular docking and bioinformatics investigation were employed. Results and Discussion: Blind docking of nine reported potential in vitro substrates with this 3D homology model revealed that substrate binding site is possibly made with PRO531, GLU507, GLU437, TRP432, ALA506, LEU519, LEU505, LEU433, GLN525, GLN510, LYS372, LYS373, SER520, SER124, SER533, SER504, SER436 amino acid residues. Virtual screening of all metabolites from the Human Serum Metabolome Database and muscle metabolites from Human Metabolite Database (HMDB) against the GLUT10 revealed possible substrates and interacting molecules for GLUT10, which were found to be involved directly or partially in ATS progression or different arterial disorders. Reported mutation screening revealed that a highly emergent point mutation (c. 1309G>A, p. Glu437Lys) is located in the predicted substrate binding site region. Conclusion: Virtual screening expands the possibility to explore more compounds that can interact with GLUT10 and may aid in understanding the mechanisms leading to ATS.

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