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The Single-Stranded DNA Binding Protein of Bacteriophage T4
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
Daniel H. Doherty, Peter Gauss, Larry Gold
Mosig has studied the effects of gene 32 missense mutants on DNA synthesis that occurs in vivo, when the T4 RNA primase activity is eliminated by a mutation in gene 61.22 This can be done because infections with amber mutations in gene 61, in an su− host, manage to make substantial amounts of DNA in the absence of the primase polypeptide. Infections by phage that carry an amber mutation in gene 61, along with one of several missense mutations in gene 32, have been analyzed. One such double (ts L171/61−) gives no DNA synthesis (even though, under the conditions used, ts L171/61+ yields high level replication). Although one might consider the ts L171 site on gp32 to reside in a domain that interacts with gp61, we think the data are more consistent with the idea that ts L171 is in a portion of gp32 whose activity is especially crucial when gp61 is missing from the infected cell. Such metabolic dependencies, rather than “protein-protein interactions”, are frequently a reasonable interpretation of genetic experiments.
Instability of Human Mitochondrial DNA, Nuclear Genes and Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
In 2013 a new enzyme PRIMPOL was described and precharacterized as a protein exhibiting two activities – primase and polymerase with unusual properties: it can by itself start DNA synthesis and is extremely resistant to DNA damage18. PRIMPOL acts both in the nucleus and mitochondrion and seems to play similar role in both compartments – it rescues stalled replication forks by adding dNTP at the site of lesion19. It does not play a role in the initiation of replication. Only one variant in PRIMPOL (4q35.1) (p.Tyr89Asp) was suggested to play role in autosomal dominant high myopia20. Although it was proven that this variant negatively influences processivity of the enzyme21 it is difficult to say whether the proposed phenotype results from alteration of nuclear, mitochondrial or both functions. Moreover, the involvement of PRIMPOL mutation in high myopia was later questioned22. The RNA polymerase involved in transcription, playing the role of primase in mtDNA replication will be presented later.
Tea Polyphenolic Compounds against Herpes Simplex Viruses
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Tin-Chun Chu, Sandra D. Adams, Lee H. Lee
Although acyclovir remains the current standard treatment for HSV-1 infections, new treatments are being developed to help combat resistant strains. Some of these treatments still focus on inhibition of viral replication but through a different process. One such class of compounds is called helicase-primase inhibitors (HPIs); these inhibit either pUL5 (helicase) or pUL52 (primase), both of which are vital to viral replication. However, mutant HSV-1 strains resistant to some of these drugs have already been detected, though a strategy of employing a combination of drugs that inhibit helicase and primase have proved successful thus far (Field and Biswas 2011; Sukla et al. 2010). Another strategy to inhibit HSV-1 propagation is to inhibit protein synthesis; trichosanthin (TCS) is a compound extracted from the root of a plant that is capable of inactivating the 60s subunit of ribosomes, thereby preventing protein synthesis. The action of TCS is believed to induce cellular apoptosis, thereby inhibiting further HSV-1 propagation (He and Tam 2010). Increased resistance resulted from taking these different drugs; novel and more effective medications need to be developed in order to prevent HSV infection (Morfin and Thouvenot 2003).
Potential therapeutic targets for Mpox: the evidence to date
Published in Expert Opinion on Therapeutic Targets, 2023
Siddappa N Byrareddy, Kalicharan Sharma, Shrikesh Sachdev, Athreya S. Reddy, Arpan Acharya, Kaylee M. Klaustermeier, Christian L Lorson, Kamal Singh
In addition to DNA polymerase, there are several other enzymatic proteins which participate in poxvirus genome replication. These include helicase-primase, and topoisomerase enzymes. Both are essential for poxvirus genome replication [25]. For example, amenamevir, a helicase-primase inhibitor of variola zoster virus has been approved in Japan, and pritelivir, an inhibitor of herpesvirus helicase-primase is in phase 3 clinical trials. Since, the poxvirus helicase-primase complex is essential for viral replication, it is an important therapeutic antiviral target. Efforts have been made to develop viral topoisomerase inhibitors. For example, (+)-Rutamarin inhibits Epstein – Barr virus topoisomerase at low micromolar IC50 [136]. The reported structure of variola virus topoisomerase can also aid in the drug-discovery efforts against MPX [137].
Drugs repurposing for SARS-CoV-2: new insight of COVID-19 druggability
Published in Expert Review of Anti-infective Therapy, 2022
Sujit Kumar Debnath, Monalisha Debnath, Rohit Srivastava, Abdelwahab Omri
Two overlapping open reading frames encode four structural proteins and sixteen nonstructural proteins (NSP) (ORFs), involved in the replication/translation process of SARS-CoV-2 [37]. The structural proteins are spike glycoprotein (S), membrane (M), nucleocapsid (N), and envelope (E). Out of them, the S protein is responsible for viral entry into the host. The nonstructural proteins include papain-like proteases (NSP3), 3-chymotrypsin like protease (3-CL or Mpro/ NSP5), endonuclease (NSP15), exoribonuclease (NSP14), helicase-triphosphatase (NSP13), primase complex (NSP7-NSP8), N7 methyltransferases (NSP10), RNA-dependent RNA polymerase (NSP12), and 2’O-methyltransferase (NSP16) [55]. Apart from these, some accessory proteins also persist in their structure. Different repurposing drugs have been explored to target these proteins to stop virus propagation (Figure 2).
Emergence of varicella-zoster virus resistance to acyclovir: epidemiology, prevention, and treatment
Published in Expert Review of Anti-infective Therapy, 2021
Kimiyasu Shiraki, Masaya Takemoto, Tohru Daikoku
Double-stranded DNA needs to be separated into two single strands (replication fork) before DNA synthesis, and complementary strands are synthesized from each DNA strand to produce two new double-stranded DNA molecules during DNA replication (Figure 3). The HP complex is responsible for unwinding viral DNA at the replication fork, separating double-stranded DNA into two single strands, and synthesizing RNA primers (Okazaki fragments) in the lagging strand for DNA synthesis. DNApol initiates complementary DNA synthesis in the two separated DNA strands. The HP complex consists of three proteins: VZVORF55 (helicase), VZVORF6 (primase), and VZVORF52 (cofactor). The helicase unwinds the duplex DNA ahead of the fork and separates the double strand into two single strands. The primase lays down RNA primers that extend the two-subunit DNApol. The HP complex possesses multienzymatic activities, including DNA-dependent ATPase, helicase, and primase activities, all of which are required for the HP complex to function in viral DNA replication.