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Biotechnology Reports (Amsterdam,... Sep 2022Synthetic peptides are in high demand as biologically active substances. Solid phase synthesis is the primary method of peptide production. However, it has drawbacks:...
Synthetic peptides are in high demand as biologically active substances. Solid phase synthesis is the primary method of peptide production. However, it has drawbacks: large amount of chemical waste and rapid increase in price with peptide length. Biosynthesis is intended as method to bypass these flaws. Direct biosynthesis is usually not effective and among other approaches for improving quality and quantity of target product fusion partners are widely used. In this study we used a thermostable chaperon-based fusion partner developed by us to produce enfuvirtide in expression system. Fusion partner's thermal stability provided additional purification mode by thermal denaturation of host proteins in lysate. Fusion protein was purified by ion exchange chromatography after lysate heating step and was then hydrolyzed with cyanogen bromide to release enfuvirtide. Enfuvirtide was isolated by RP-HPLC up to 94% purity with total yield of 2.86-3.31 mg per 1 L of low-density culture. The data demonstrate the posibility of thermostable chaperone-based fusion partner GroEL use for effective peptide biosynthesis.
PubMed: 35646620
DOI: 10.1016/j.btre.2022.e00734 -
Clinical Microbiology and Infection :... Mar 2003Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral... (Review)
Review
Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral drugs are needed to improve convenience, reduce toxicity and, of particular importance, to provide antiretroviral activity against viral strains resistant to the currently available antiretroviral agents. Candidate drugs with novel properties are in development in the two currently available drug classes: HIV reverse transcriptase inhibitors (nucleoside analogs, non-nucleoside analogs and nucleotide analogs) and HIV protease inhibitors (PI). Investigational nucleoside analog reverse transcriptase inhibitors (nRTI) include emtricitabine (FTC) and amdoxovir (DAPD), and investigational non-nucleoside reverse transcriptase inhibitors (NNRTI) include DPC 083 and TMC 125. New protease inhibitors under investigation include atazanavir (BMS-232 632), tipranavir, and TMC 114. In addition, newer agents with novel mechanisms of action such as HIV entry inhibitors (that inhibit the three steps of HIV entry: CD4 attachment, chemokine receptor binding and membrane fusion) and HIV integrase inhibitors are under investigation. Investigational entry inhibitors include PRO 542 (a CD4 attachment inhibitor), Schering C (a chemokine receptor inhibitor), enfuvirtide (T-20) and T-1249, inhibitors of membrane fusion. Investigational HIV integrase inhibitors include S-1360. Continued progress in the treatment of HIV disease will result from the development of new antiretroviral drugs.
Topics: Anti-HIV Agents; Drug Design; Drug Therapy, Combination; HIV Fusion Inhibitors; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Reverse Transcriptase Inhibitors
PubMed: 12667250
DOI: 10.1046/j.1469-0691.2003.00570.x -
Expert Review of Anti-infective Therapy Oct 2021: There are currently no specific drugs and universal vaccines for Coronavirus disease 2019 (COVID-19), hence urgent effective measures are needed to discover and... (Review)
Review
: There are currently no specific drugs and universal vaccines for Coronavirus disease 2019 (COVID-19), hence urgent effective measures are needed to discover and develop therapeutic agents. Applying peptide therapeutics and their related compounds is a promising strategy to achieve this goal. This review is written based on the literature search using several databases, previous studies, scientific reports, our current knowledge about the antimicrobial peptides (AMPs), and our personal analyses on the potential of the antiviral peptides for the treatment of COVID-19.: In this review, we begin with a brief description of SARS-CoV2 followed by a comprehensive description of antiviral peptides (AVPs) including natural and synthetic AMPs or AVPs and peptidomimetics. Subsequently, the structural features, mechanisms of action, limitations, and therapeutic applications of these peptides are explained.: Regarding the lack and the limitations of drugs against COVID-19, AMPs, AVPs, and other peptide-like compounds such as peptidomimetics have captured the attention of researchers due to their potential antiviral activities. Some of these compounds comprise unique properties and have demonstrated the potential to fight SARS-CoV2, particularly melittin, lactoferrin, enfuvirtide, and rupintrivir that have the potential to enter animal and clinical trials for the treatment of COVID-19.
Topics: Antimicrobial Cationic Peptides; Antiviral Agents; COVID-19; Cathelicidins; Computer Simulation; Defensins; Hepcidins; Humans; Lactoferrin; Melitten; Molecular Structure; Peptidomimetics; SARS-CoV-2; Viral Structures; COVID-19 Drug Treatment
PubMed: 33844613
DOI: 10.1080/14787210.2021.1912593 -
Drugs in Context 2018A review of literature published regarding non-tenofovir antiretroviral agents causing renal adverse effects was conducted. The literature involving renal adverse... (Review)
Review
A review of literature published regarding non-tenofovir antiretroviral agents causing renal adverse effects was conducted. The literature involving renal adverse effects and antiretroviral therapy is most robust with protease inhibitors, specifically atazanavir and indinavir, and includes reports of crystalluria, leukocyturia, nephritis, nephrolithiasis, nephropathy and urolithiasis. Several case reports describe potential nephropathy (including Fanconi syndrome) secondary to administration of abacavir, didanosine, lamivudine and stavudine. Case reports documented renal events such as acute renal failure, nephritis, proteinuria and renal stones with efavirenz administration. Regarding rilpivirine, a small increase of serum creatinine levels (SCr) was found in clinical trials; however, the clinical significance and impact on actual renal function is unknown. The integrase strand transfer inhibitors and enfuvirtide have a relatively safe renal profile, although studies have shown dolutegravir and raltegravir cause mild elevations in SCr without an impact on actual renal function. This is similar to the reaction observed with cobicistat, the pharmacokinetic enhancer frequently given with elvitegravir.
PubMed: 29623097
DOI: 10.7573/dic.212519 -
Advanced Drug Delivery Reviews Aug 2016In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central... (Review)
Review
In spite of significant advances in antiretroviral (ARV) therapy, the elimination of human immunodeficiency virus (HIV) reservoirs from the periphery and the central nervous system (CNS) remains a formidable task. The incapability of ARV to go across the blood-brain barrier (BBB) after systemic administration makes the brain one of the dominant HIV reservoirs. Thus, screening, monitoring, and elimination of HIV reservoirs from the brain remain a clinically daunting and key task. The practice and investigation of nanomedicine possesses potentials for therapeutics against neuroAIDS. This review highlights the advancements in nanoscience and nanotechnology to design and develop specific size therapeutic cargo for efficient navigation across BBB so as to recognize and eradicate HIV brain reservoirs. Different navigation and drug release strategies, their biocompatibility and efficacy with related challenges and future prospects are also discussed. This review would be an excellent platform to understand nano-enable multidisciplinary research to formulate efficient nanomedicine for the management of neuroAIDS.
Topics: AIDS Dementia Complex; Anti-HIV Agents; Blood-Brain Barrier; Brain; HIV; Humans; Nanomedicine
PubMed: 26944096
DOI: 10.1016/j.addr.2016.02.008 -
Frontiers in Microbiology 2022HIV envelope transmembrane glycoproteins gp41 (HIV-1) and gp36 (HIV-2) present high variability and play a key role in the HIV-host cell membrane's fusion, as a target...
HIV envelope transmembrane glycoproteins gp41 (HIV-1) and gp36 (HIV-2) present high variability and play a key role in the HIV-host cell membrane's fusion, as a target for human broadly neutralizing antibodies (bnAbs) and drugs. Thus, a better knowledge of amino acid (aa) conservation across structural domains and HIV variants can help to identify conserved targets to direct new therapeutic and diagnostic strategies. All available gp41/gp36 nucleotide sequences were downloaded from Los Alamos National Laboratory (LANL) HIV Sequence Database, selecting 17,078 sequences ascribed to HIV-1 and HIV-2 variants with ≥3 sequences. After aligning and translating into aa with MEGAv6.0, an in-house bioinformatics program (EpiMolBio) was used to identify the most conserved aa and the aa changes that were specific for each variant (V-markers) . HXB2/BEN (HIV-1/HIV-2) reference sequence. We analyzed the presence of specific aa changes among V-markers affecting infectivity, gp41 structure, function, or resistance to the enfuvirtide viral fusion inhibitor (T-20). We also inferred the consensus sequences per HIV variant, describing in each HIV-1 group (M, N, O, P) the conservation level along the complete gp41 per structural domain and locating in each binding site the anti-gp41 human Abs (bnAbs and non bnAbs) described in LANL. We found 38.3/59.7% highly conserved aa present in ≥90% of the 16,803/275 gp41/gp36 sequences ascribed to 105/3 HIV-1/HIV-2 variants, with 9/12.6% of them showing complete conservation across LANL sequences. The fusion peptide, its proximal region, the N-heptad repeat, and the membrane-proximal external region were the gp41 domains with ≥84% of conserved aa in the HIV-1 consensus sequence, the target of most Abs. No natural major resistance mutations to T-20 were observed. Our results show, for the first time, a complete conservation study of gp41/gp36 per variant in the largest panel of HIV variants analyzed to date, providing useful information for a more rational design of drugs, vaccines, and molecular detection tests targeting the HIV transmembrane glycoprotein.
PubMed: 35694284
DOI: 10.3389/fmicb.2022.855232 -
Frontiers in Microbiology 2020Infectious diseases caused by human immunodeficiency virus (HIV) and other highly pathogenic enveloped viruses, have threatened the global public health. Most antiviral... (Review)
Review
Infectious diseases caused by human immunodeficiency virus (HIV) and other highly pathogenic enveloped viruses, have threatened the global public health. Most antiviral drugs act as passive defenders to inhibit viral replication inside the cell, while a few of them function as gate keepers to combat viruses outside the cell, including fusion inhibitors, e.g., enfuvirtide, and receptor antagonists, e.g., maraviroc, as well as virus inactivators (including attachment inhibitors). Different from fusion inhibitors and receptor antagonists that must act in the presence of target cells, virus inactivators can actively inactivate cell-free virions in the blood, through interaction with one or more sites in the envelope glycoproteins (Envs) on virions. Notably, a number of protein- and peptide-based virus inactivators (PPVIs) under development are expected to have a better utilization rate than the current antiviral drugs and be safer for human application than the chemical-based virus inactivators. Here we have highlighted recent progress in developing PPVIs against several important enveloped viruses, including HIV, influenza virus, Zika virus (ZIKV), dengue virus (DENV), and herpes simplex virus (HSV), and the potential use of PPVIs for urgent treatment of infection by newly emerging or re-emerging viruses.
PubMed: 32523582
DOI: 10.3389/fmicb.2020.01063